Imidazopyridine derivatives, process for preparation thereof and therapeutic use thereof

ABSTRACT

The invention relates to compounds corresponding to formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             in which
           R 2  and R 3  together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to one of formula (A), (B) or (C) below:   
         
           
         
       
    
     
       
         
         
             
             
         
       
     
     in which the wavy lines represent the phenyl nucleus to which R 2  and R 3  are attached. 
     Preparation process and therapeutic use.

The present invention relates to imidazopyridine derivatives which areinhibitors of FGFs (Fibroblast Growth Factors), to the process for thepreparation thereof and to the therapeutic use thereof.

FGFs are a family of polypeptides synthesized by a large number of cellsduring embryonic development and by cells of adult tissues in variouspathological conditions.

Indolizine derivatives, which are antagonists of the binding of FGFs totheir receptors, are described in international patent applications WO03/084956 and WO 2005/028476. Imidazo[1,5-a]pyridine derivatives whichare FGF antagonists are described in international patent application WO2006/097625. Novel imidazopyridine derivatives, which are antagonists ofthe binding of FGFs to their receptors, have now been identified.

The subject of the present invention is thus compounds, imidazopyridinederivatives, corresponding to formula (I):

in which:

-   -   R₁ represents        -   a hydrogen or halogen atom,        -   an alkyl group optionally substituted with —COOR₅,        -   an alkenyl group optionally substituted with —COOR₅,        -   a —COOR₅ or —CONR₅R₆ group,        -   an —NR₅COR₆ or —NR₅—SO₂R₆ group,        -   or        -   an aryl group, in particular phenyl, or a heteroaryl group,            said aryl or heteroaryl group being optionally substituted            with one or more groups selected from: halogen atoms, alkyl            groups, cycloalkyl groups, —COOR₅, —CF₃, —OCF₃, —CN,            —C(NH₂)NOH, —OR₅, —O-Alk-COOR₅, —O-Alk-NR₅R₆, —O-Alk-NR₇R₈,            -Alk-OR₅, -Alk-COOR₅, —CONR₅R₆, —CO—NR₅—OR₆, —CO—NR₅—SO₂R₇,            —CONR₅-Alk-NR₅R₆, —CONR₅-Alk-NR₇R₈, -Alk-NR₅R₆, —NR₅R₆,            —NC(O)N(CH₃)₂, —CO-Alk, —CO(OAlk)_(n)OH, COO-Alk-NR₅R₆,            COO-Alk-NR₇R₈ and 5-membered heteroaryl groups, said            heteroaryl groups being optionally substituted with one or            more groups selected from halogen atoms and alkyl, —CF₃,            —CN, —COOR₅, -Alk-OR₅, -Alk-COOR₅, —CONR₅R₆, —CONR₇R₈,            —CO—NR₅—OR₆, —CO—NR₅—SO₂R₆, —NR₅R₆ and -Alk-NR₅R₆ groups, or            with a hydroxyl group or with an oxygen atom,    -   n is an integer ranging from 1 to 3,    -   R₂ and R₃ together form, with the carbon atoms of the phenyl        nucleus to which they are attached, a 6-membered nitrogenous        heterocycle corresponding to one of formula (A), (B) or (C)        below:

-   -   in which the wavy lines represent the phenyl nucleus to which R₂        and R₃ are attached and:        -   R_(a) represents a hydrogen atom or an alkyl, haloalkyl,            -Alk-CF₃, -Alk-COOR₅, -Alk′-COOR₅, -Alk-CONR₅R₆,            -Alk′-CONR₅R₆, -Alk-CONR₇R₈, -Alk-NR₅R₆, -AlkCONR₅—OR₆,            -Alk-NR₇R₈, -Alk-cycloalkyl, -Alk-O—R₅, -Alk-S—R₅, -Alk-CN,            —OR₅, -OAlkCOOR₅, —NR₅R₆, —NR₅—COOR₆, -Alk-aryl,            -Alk-O-aryl, -Alk-O-heteroaryl, -Alk-heteroaryl or            heteroaryl group, where the aryl or heteroaryl group is            optionally substituted with one or more halogen atoms and/or            alkyl, cycloalkyl, —CF₃, —OCF₃, —O—R₅ or —S—R₅ groups,        -   R_(a) represents a hydrogen atom or a linear, branched,            cyclic or partially cyclic alkyl group, or an -Alk-OR₅,            -Alk-NR₅R₆ or -Alk-NR₇R₈ group, R_(a′) being optionally            substituted with one or more halogen atoms,        -   R_(b) represents a hydrogen atom or an alkyl or -Alk-COOR₅            group,        -   R_(b′) represents a hydrogen atom or an alkyl, haloalkyl,            cycloalkyl, phenyl or -Alk-COOR₅ group,        -   R_(c) represents a hydrogen atom or an alkyl, —CN, —COOR₅,            —CO—NR₅R₆, —CONR₇R₈—CO—NR₅-Alk-NR₅R₆, —CONR₅-Alk-OR₅,            —CONR₅SO₂R₅, -Alk-aryl or -Alk-heteroaryl group, where the            aryl or heteroaryl group is optionally substituted with one            or more halogen atoms and/or alkyl, cycloalkyl, —CF₃, —OCF₃,            —O-alkyl or —S-alkyl groups,        -   R_(c′) represents a hydrogen atom or an alkyl group,        -   R_(c″) represents a hydrogen atom or an alkyl, alkenyl,            haloalkyl, cycloalkyl, -Alk-NR₅R₆, -Alk-NR₇R₈, -Alk-OR₅ or            -Alk-SR₅ group,    -   R₄, located on position 6, 7 or 8 of the imidazopyridine        nucleus, represents:        -   a hydrogen atom,        -   a —COOR₅ group,        -   a —CO—NR₅-Alk-NR₅R₆ group,        -   a —CO—NR₅-Alk-NR₇R₈ group, or        -   a —CO—NR₅-Alk-OR₆ group,    -   R₅ and R₆, which may be identical or different, represent        hydrogen atoms, haloalkyl groups or alkyl groups, cycloalkyl        groups or an Ms (mesyl) group,    -   R₇ and R₈, which may be identical or different, represent        hydrogen atoms or alkyl or phenyl groups, or else R₇ and R₈        together form a 3- to 8-membered saturated ring which can        optionally contain a heteroatom,    -   Alk represents a linear or branched alkylene chain, and    -   Alk′ represents a linear, branched, cyclic or partially cyclic        alkylene chain,    -   these compounds being optionally present in the form of a        pharmaceutically acceptable salt thereof.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They can therefore exist in the form of enantiomers or ofdiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures, are part of the invention.

The compounds of formula (I) can exist in the form of bases or of acidsor can be salified with acids or bases, in particular pharmaceuticallyacceptable acids or bases. Such addition salts are part of theinvention. These salts are advantageously prepared with pharmaceuticallyacceptable acids or bases, but the salts of other acids or bases thatare of use, for example, for purifying or isolating the compounds offormula (I) are also part of the invention.

The compounds of formula (I) can also exist in the form of hydrates orof solvates, namely in the form of associations or combinations with oneor more molecules of water or with a solvent. Such hydrates or solvatesare also part of the invention.

In the context of the invention, and unless otherwise mentioned in thetext, the term:

-   -   “alkyl” is intended to mean: a linear or branched, saturated        hydrocarbon-based aliphatic group containing from 1 to 6 carbon        atoms;    -   “cycloalkyl” is intended to mean: a cyclic alkyl group        comprising from 3 to 8 ring members, containing between 3 and 6        carbon atoms and optionally comprising one or more heteroatoms,        for example 1 or 2 heteroatoms, such as nitrogen and/or oxygen,        said cycloalkyl group being optionally substituted with one or        more halogen atoms and/or alkyl groups. By way of examples,        mention may be made of cyclopropyl, cyclopentyl, piperazinyl,        pyrrolidinyl and piperidinyl groups;    -   “partially cyclic alkyl group” is intended to mean: an alkyl        group of which only a part forms a ring;    -   “alkylene” is intended to mean: a linear or branched divalent        alkyl group containing from 1 to 6 carbon atoms;    -   “halogen” is intended to mean: a chlorine, fluorine, bromine or        iodine atom;    -   “haloalkyl” is intended to mean: an alkyl chain in which all or        some of the hydrogen atoms are replaced with halogen atoms, such        as fluorine atoms;    -   “aryl” is intended to mean: a cyclic aromatic group containing        between 5 and 10 carbon atoms, for example a phenyl group;    -   “heteroaryl” is intended to mean: a cyclic aromatic group        containing between 3 and 10 atoms, including one or more        heteroatoms, for example between 1 and 4 heteroatoms, such as        nitrogen, oxygen or sulphur, this group comprising one or more,        preferably one or two, rings. The heterocycles may comprise        several condensed rings. The heteroaryls are optionally        substituted with one or more alkyl groups or an oxygen atom. By        way of examples, mention may be made of thienyl, pyridinyl,        pyrazolyl, imidazolyl, thiazolyl and triazolyl groups; and    -   “5-membered heteroaryl” is intended to mean: a heteroaryl group        consisting of a 5-membered ring comprising 1 to 4 heteroatoms        (such as oxygen and/or nitrogen atoms), optionally substituted        with one or more alkyl groups or a hydroxyl group or with an        oxygen atom. Mention may, for example, be made of oxadiazolyl        and tetrazolyl groups;    -   the halogens are preferably selected from F and Cl.

Among the compounds of formula (I) according to the invention, mentionmay be made of a subgroup of compounds in which R₁ represents:

-   -   a hydrogen or halogen atom,    -   an alkyl group which is unsubstituted or substituted with        —COOR₅,    -   an alkenyl group which is unsubstituted or substituted with        —COOR₅,    -   a —COOR₅ group,    -   a —CONR₅R₆ group,    -   an —NR₅—SO₂R₆ group, or    -   a phenyl group optionally substituted with one or two groups        selected from:        -   halogen atoms;        -   alkyl groups optionally substituted with —COOR₅;        -   —CN (cyano), —C(NH₂)NOH, —COOR₅, —CONR₅R₆, —CO—NR₅—OR₆,            —CO—NR₅—SO₂R₆, —COAlk, —CO(OAlk)_(n)OH, —OR₅, —OCF₃,            —O-Alk-COOR₅, -Alk-OR₅, —NR₅R₆ or —NC(O)N(CH₃)₂ groups,        -   5-membered heteroaryls optionally substituted with an alkyl            group and/or a hydroxyl group or an oxygen atom,    -   in which R₅ and R₆, which may be identical or different,        represent hydrogen atoms, or alkyl groups optionally substituted        with an —NR₇R₈ group,    -   R₇ represents a hydrogen atom, an alkyl group containing 1 or 2        carbon atoms or a phenyl group, n is an integer ranging from 1        to 3, or    -   a heteroaryl group which is optionally condensed and/or        optionally substituted with one or two groups selected from        alkyl groups, OR₅, —COOR₅, —NR₅R₆ and cycloalkyl groups, and an        oxygen atom, in which R₅ and R₆, which may be identical or        different, represent hydrogen atoms or alkyl groups containing 1        or 2 carbon atoms.

Among the compounds of formula (I) according to the invention, mentionmay be made of another subgroup of compounds in which R₂ and R₃ togetherform, with the carbon atoms of the phenyl nucleus to which they areattached, a 6-membered nitrogenous heterocycle corresponding to eitherof formulae (A) and (B) defined above, preferably corresponding toformula (A).

Formula (A) or (B) is advantageously such that:

-   -   R_(a) represents a hydrogen atom or an alkyl group, optionally        substituted with one or more halogens; -AlkCONR₅R₆; haloalkyl;        —CH₂—COOR₅; -Alk-heteroaryl, -Alk-O-phenyl or -Alk-phenyl, where        the phenyl group is optionally substituted with one or two alkyl        groups and/or OR₅ and/or halogen atoms; -Alk-cycloalkyl,    -   R_(a′) represents a hydrogen atom or a linear, branched, cyclic        or partially cyclic alkyl group, or a —CH₂—OR₅ or -Alk-NR₅R₆        group,    -   R_(b) represents a hydrogen atom or an alkyl group,    -   R_(b′) represents a hydrogen atom or an alkyl, phenyl or        —CH₂—COOR₅ group,    -   in which the alkyl groups contain 1 to 6 carbon atoms, R₅ being        as defined above.

Among the compounds of formula (I) according to the invention, mentionmay be made of another subgroup of compounds in which R₄ represents ahydrogen atom or a —COOH, —CO—NH-Alk-NR₇R₈ or —CO—NH-Alk-OH group, inwhich Alk, R₇ and R₈ are as defined above, or else an alkyl group,preferably containing 1 to 3 carbon atoms, which is unsubstituted.

In the compounds of formula (I) according to the invention, R₄ isadvantageously located on position 6 or 7 of the imidazopyridinenucleus.

Among the compounds which are subjects of the invention, mention may bemade of the following compounds:

-   5-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}-2-fluorobenzoic    acid-   3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic    acid-   3-{3-[(1-methyl-2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic    acid-   3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic    acid-   3-(3-{[3-(4-fluorobenzyl)-1-(methoxymethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic    acid-   3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic    acid-   3-[3-({3-[2-(4-fluorophenyl)ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic    acid-   3-[3-({1-methyl-3-[(5-methylthiophen-2-yl)methyl]-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic    acid-   3-[3-({3-[(5-methylthiophen-2-yl)methyl]-2,4-dioxo-1-propyl-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic    acid-   3-(3-{[2,4-dioxo-1-propyl-3-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic    acid-   3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic    acid

In the following text, the term “protective group” is intended to mean agroup which makes it possible, firstly, to protect a reactive functionsuch as a hydroxyl or an amine during a synthesis and, secondly, toregenerate the intact reactive function at the end of synthesis.Examples of protective groups and also methods of protection anddeprotection are given in “Protective Groups in Organic Synthesis”,Green et al., 3^(rd) Edition (John Wiley & Sons, Inc., New York).

In the remainder of the text, the term “leaving group” is intended tomean a group that can be readily cleaved from a molecule by breaking aheterolytic bond, with the departure of a pair of electrons. This groupcan thus be readily replaced with another group during a substitutionreaction, for example. Such leaving groups are, for example, halogens oran activated hydroxyl group, such as a mesyl, tosyl, triflate, acetyl,para-nitrophenyl, etc. Examples of leaving groups and also methods forthe preparation thereof are given in “Advances in Organic Chemistry”, J.March, 3^(rd) Edition, Wiley Interscience, p. 310-316.

In accordance with the invention, the compounds of general formula (I)can be prepared according to the processes hereinafter.

The compounds of formula (IV) are obtained by methods known in theliterature, starting from the suitably substituted corresponding2-aminomethylpyridines, according to the following reaction scheme,described in J. Chem. Soc. (1955), 2834-2836

When R₄ represents COOR₅, the compounds of formula (II) are obtainedaccording to the reaction scheme described in WO 06/097625.

Scheme 1 presents a pathway for obtaining the compounds of formula (I)in which R₂ and R₃ together form a nitrogenous heterocycle of formula(A) as defined above, and in which R₁ and R_(a′) represent hydrogenatoms.

The compound of formula (IV), in which R₄ is as defined for the compoundof formula I, is condensed with the compound of formula V in order toobtain the compound of formula VI. The compound of formula VI issubjected to a basic hydrolysis reaction in order to obtain the compoundof formula VII. The esterification of the compound of formula VIIproduces the compound of formula VIII. By reacting triphosgene, theisocyanate corresponding to the compound of formula VIII is formed,which is condensed with an amine of formula R_(a)NH₂ in order to obtainthe urea of formula IX. The compound of formula IX is subjected to acyclization reaction in a basic medium in order to obtain the compoundof formula I in which R₄ and R_(a) are as defined above.

Scheme 2 presents a pathway for obtaining the compounds of formula (I)in which R₂ and R₃ together form a nitrogenous heterocycle of formula(A) as defined above, and in which R₁ represents a group as defined inthe general formula, except for a hydrogen atom.

The compound of formula VIII is subjected to a bromination reaction inorder to obtain the compound of formula X. By reacting triphosgene, theisocyanate corresponding to the compound of formula X is formed, whichis condensed with an amine of formula R_(a)NH₂ in order to obtain theurea of formula XI. The compound of formula XI is subjected to acyclization reaction in a basic medium, in order to obtain the compoundof formula XII. The compound XII is subjected to an alkylation reactionin the presence of a base and of a halogenated derivative Ra′X in orderto obtain the compound of formula XIII. The compound of formula XIII issubjected, in the presence of a palladium catalyst, of a ligand and of abase,

-   -   to a reaction with phenylboronic or heteroarylboronic or        phenylboronate ester or heteroarylboronate ester derivatives        according to a Suzuki coupling,    -   or else to an imination reaction with benzophenoneimine followed        by an acid hydrolysis and by an alkylation reaction with a        suiphonyl chloride of formula R₆SO₂Cl,    -   or else to a cyanation reaction with zinc cyanide, followed by        an acid hydrolysis and by an esterification or a peptide        coupling with an amine R₅R₆NH₂,        in order to obtain the compound of formula I in which R₁, R₄,        R_(a) and R_(a′) are as defined above.

Scheme 3 presents a pathway for obtaining the compounds of formula (I)in which R₂ and R₃ together form a nitrogenous heterocycle of formula(A) as defined above, and in which R₁ represents a group as defined inthe general formula, except for a hydrogen atom, and in which R₄ is asdefined above.

The compound of formula X is subjected, in the presence of a palladiumcatalyst, of a ligand and of a base,

-   -   to a reaction with phenylboronic or heteroarylboronic or        phenylboronate ester or heteroarylboronate ester derivatives        according to a Suzuki coupling,    -   or else to an imination reaction with benzophenoneimine,        followed by an acid hydrolysis and by an alkylation reaction        with a suiphonyl chloride of formula R₆SO₂Cl,    -   or else to a cyanation reaction with zinc cyanide, followed by        an acid hydrolysis and by an esterification or a peptide        coupling with an amine R₅R₆NH₂, R₅ and R₆ being defined above,        in order to obtain the compound of formula XIV in which R₁ is as        defined above. By reacting triphosgene, the isocyanate        corresponding to the compound of formula XIV is formed, which is        condensed with an amine of formula R_(a)NH₂ in order to obtain        the urea of formula XV. The compound of formula XV is subjected        to a cyclization reaction in a basic medium in order to obtain        the compound of formula XVI. The compound XVI is subjected to an        alkylation reaction in the presence of a base and of a        halogenated derivative R_(a′)X in order to obtain the compound        of formula I.

Scheme 4 presents a pathway for obtaining the compounds of formula (I)in which R₂ and R₃ together form a nitrogenous heterocycle of formula(A) as defined above, and in which R₁ represents a group as defined inthe general formula, except for a hydrogen atom, and in which R₄ is asdefined above.

The compound of formula XII is subjected, in the presence of a palladiumcatalyst, of a ligand and of a base,

-   -   to a reaction with phenylboronic or heteroarylboronic or        phenylboronate ester or heteroarylboronate ester derivatives        according to a Suzuki coupling,    -   or else to an imination reaction with benzophenoneimine,        followed by an acid hydrolysis and by a sulphonylation reaction        with a sulphonyl chloride of formula R₆SO₂Cl,    -   or else to a cyanation reaction with zinc cyanide, followed by        an acid hydrolysis and by an esterification or a peptide        coupling with an amine R₅R₆NH₂,        in order to obtain the compound of formula XVI in which R₁ is as        defined above. The compound XVI is subjected to an alkylation        reaction in the presence of a base and of a halogenated        derivative R_(a′)X in order to obtain the compound of formula I.

Scheme 5 presents a pathway for obtaining the compounds of formula (I)in which R₂ and R₃ together form a nitrogenous heterocycle of formula(B) as defined above, in which R₁ represents a hydrogen atom and inwhich R₄ is as defined above.

The compound VIII is subjected to a saponification reaction in order toobtain the compound XXIV. The compound XXIV is subsequently subjected toa condensation reaction with an alkyl or aryl anhydride (R_(b′)CO)₂O inorder to obtain the compound of formula XVII. The compound of formulaXVII is subjected to a condensation reaction with an amine R_(b)NH₂ inorder to obtain a compound of formula I in which R_(b) and R_(b′) are asdefined above.

Scheme 6 presents a pathway for obtaining the compounds of formula (I)in which R₂ and R₃ together form a nitrogenous heterocycle of formula(B) as defined above and in which R₁ is as defined above, except for ahydrogen, and in which R₄ is as defined above.

The compound XIV is subjected to a saponification reaction in order toobtain the compound XXV. The compound XXV is subsequently subjected to acondensation reaction with an alkyl or aryl anhydride (R_(b′)CO)₂O inorder to obtain the compound of formula XVIII. The compound of formulaXVIII is subjected to a condensation reaction with an amine R_(b)NH₂ inorder to obtain a compound of formula I in which R_(b) and R_(b′) are asdefined above.

Scheme 7 presents a pathway for obtaining the compounds of formula (I)in which R₂ and R₃ together form a nitrogenous heterocycle of formula(C) as defined above and in which R_(c″) and also R₁ and R₄ are asdefined above.

The compound X is subjected to a saponification reaction in order toobtain the compound XIX. The compound XIX is subjected to a condensationreaction in the presence of triphosgene, in order to obtain the compoundXX. The compound XX is subjected to an alkylation reaction in thepresence of a halogenated derivative R_(c″)X or of a protective group inorder to obtain the compound XXI. The compound XXI is subjected to acondensation reaction with a malonic derivative in order to obtain thecompound XXII in which R_(c′) and R_(c) are as defined above. Thecompound XXII is subjected, in the presence of a palladium catalyst, ofa ligand and of a base,

-   -   to a reaction with phenylboronic or heteroarylboronic or        phenylboronate ester or heteroarylboronate ester derivatives        according to a Suzuki coupling,    -   or else to an imination reaction with benzophenoneimine,        followed by an acid hydrolysis and by a sulphonylation reaction        with a sulphonyl chloride of formula R₆SO₂Cl,    -   or else to a cyanation reaction with zinc cyanide, followed by        an acid hydrolysis and by an esterification or a peptide        coupling with an amine R₅R₆NH₂,        in order to obtain the compound of formula XXIII in which R₁ is        as defined above.

The compound XXIII is subjected to a deprotection reaction in order toobtain the compounds of formula I in which R_(c″) is a hydrogen atom.

In the preceding schemes, the starting compounds and the reactants, whenthe method for preparing them is not described, are commerciallyavailable or described in the literature, or else can be preparedaccording to methods which are described therein or which are known tothose skilled in the art.

A subject of the invention, according to another of its aspects, is alsothe compounds of formulae II to XXIII defined above. These compounds areof use as synthesis intermediates for the compounds of formula (I).

The following examples describe the preparation of certain compounds inaccordance with the invention. These examples are not limiting andmerely illustrate the present invention. The numbers of the compoundsexemplified refer back to those given in the table hereinafter, whichillustrates the chemical structures and the physical properties of somecompounds according to the invention.

The reactants and intermediates, when their preparation is notexplained, are known in the literature or commercially available. Someintermediates that are of use for preparing the compounds of formula Imay also serve as final products of formula (I), as will become apparentin the examples given hereinafter. Similarly, some compounds of formula(I) of the invention can serve as intermediates that are of use forpreparing other compounds of formula (I) according to the invention.

By way of example, the derivatives of formula (I) are selected from thefollowing compounds:

-   6-(imidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dione,-   3-{3-[4(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic    acid,-   3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridine-6-carboxylic    acid,-   3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic    acid,-   3-{3[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzamide,-   6-({1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl-3-propylquinazoline-2,4(1H,3H)-dione,-   6-({1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-3-propylquinazoline-2,4(1H,3H)-dione,-   N-{3-[4(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}methanesulphonamide,-   2-morpholin-4-yl-ethyl    3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate,-   N-[2-(dimethylamino)ethyl]-3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzamide,-   3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic    acid,-   3-(4-fluorobenzyl)-1-methyl-6-[(1-pyridin-3-ylimidazo[1,5-a]pyridin-3-yl)carbonyl]quinazoline-2,4(1H,3H)-dione,-   3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic    acid,-   3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzamide,-   6-(imidazo[1,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3H)-one,-   N,N,1,2-tetramethyl-4-oxo-6-{[1-(pyridin-3-yl)imidazo[1,5-a]pyridin-3-yl]carbonyl}-1,4-dihydroquinoline-3-carboxamide,-   3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic    acid.

ABBREVIATIONS

TOTU:O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

NMP: N-Methylpyrrolidone

DME: Ethylene glycol dimethyl ether

DMF: Dimethylformamide THF: Tetrahydrofuran

Binap: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

The NMR analyses were carried out on Bruker Avance 250 MHz, 300 MHz and400 MHz instruments.

-   -   The melting points were measured on a Buchi B-450 instrument.    -   The mass spectrometry analyses were carried out on a Waters        Alliance 2695 (UV: PDA996, MS: LCZ), Alliance 2695 (UV: PDA 996,        MS: ZQ (simple Quad) ZQ1), Alliance 2695 (UV: PDA 996, MS: ZQ        (simple Quad) ZQ2), Waters UPLC Acquity (UV: Acquity PDA, MS:        SQD (simple Quad) SQW), Agilent MSD, Waters ZQ, or Waters SQD        instrument.

EXAMPLE 1 Compound No. 16-(Imidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dioneMethyl 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate

13.4 ml (96 mmol) of triethylamine are added to 3.5 g (30 mmol) ofimidazo[1,5-a]pyridine [described in J. Chem. Soc.; (1955), 2834-2836]in 250 ml of 1,2-dichloroethane, followed, under a nitrogen atmosphereat 0° C., by 13.7 g (48 mmol) of4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride (described in WO05/028476). After stirring for 4.5 hours at ambient temperature, thereaction medium is filtered. The residue obtained is washed with1,2-dichloroethane. After drying overnight at 40° C. under reducedpressure, 3 g of a yellow solid are obtained.

The residue obtained is dissolved in 100 ml of NMP. A solution of 8.4 g(0.15 mol) of KOH in 10 ml of water is added dropwise, under a nitrogenatmosphere, at ambient temperature. The reaction medium is heated at 80°C. for 6 hours and then poured, at ambient temperature, into a 1Naqueous solution of hydrochloric acid. The precipitate obtained isfiltered off, rinsed with water and then dried at 40° C. under reducedpressure overnight. After silica gel column chromatography, elutionbeing carried out with a dichloromethane/methanol/0.1% triethylaminemixture, 5.5 g of a yellow solid are obtained.

7 g (0.022 mol) of caesium carbonate and then, dropwise, 1.34 ml (0.022mol) of methyl iodide are added, under a nitrogen atmosphere at ambienttemperature, to 5.5 g (0.02 mol) of the residue obtained, in 100 ml ofDMF. After stirring for 24 hours at ambient temperature, the reactionmedium is poured into water. The precipitate obtained is filtered off,rinsed with water and then dried overnight at 40° C. under reducedpressure. 5.1 g of a yellow solid are obtained.

Melting point: 192° C.

MH+: 296

Methyl5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)-2-[(propylcarbamoyl)amino]benzoate

0.35 g (1.2 mmol) of triphosgene is added, at ambient temperature undera nitrogen atmosphere, to a suspension of 0.5 g (1.7 mmol) of methyl2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml ofanhydrous dioxane. After heating for 2 hours at 100° C., 0.28 ml (3.4mmol) of n-propylamine and then 0.71 ml (5 mmol) of triethylamine areadded to the reaction medium at ambient temperature. After stirring for18 hours at ambient temperature, H₂O is added. The aqueous phase isextracted with dichloromethane. The organic phase is dried over sodiumsulphate, filtered, and concentrated under reduced pressure. The yellowsolid obtained is purified by silica gel column chromatography, elutionbeing carried out with a dichloromethane/methanol (98/2) mixture. 0.410g of a yellow solid is obtained.

Melting point: 205° C.

MH+: 381

6-(Imidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dione

1.38 ml (1.38 mmol) of a 1N aqueous solution of sodium hydroxide areadded, at ambient temperature, to a suspension of 0.436 g (1.15 mmol) ofmethyl5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)-2-[(propylcarbamoyl)amino]benzoatein 10 ml of methanol. After refluxing for 2 hours, the methanol isconcentrated under reduced pressure. A 1N aqueous solution ofhydrochloric acid is added. The precipitate obtained is filtered off,rinsed with water and then dried overnight at 40° C. under reducedpressure. 0.27 g of a yellow solid is obtained.

Melting point: 304° C.

¹H-NMR (D6-DMSO, 400 MHz):

0.91 (t, J=7.17 Hz, 3H), 1.63 (q, J=7.59 Hz, 2H), 3.89 (t, J=7.17 Hz,2H), 7.25-7.37 (m, 2H), 7.39-7.43 (m, 1H), 7.82 (s, 1H), 7.97 (d, J=8.86Hz, 1H), 8.59 (d, J=8.86 Hz, 1H), 9.18 (s, 1H), 9.74 (d, J=7.17 Hz, 1H),11.8 (s, 1H).

EXAMPLE 2 Compound No. 10 Sodium Salt of3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid Methyl2-amino-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate

0.42 g (2.4 mmol) of N-bromosuccinimide is added, under a nitrogenatmosphere at ambient temperature, to a solution of 0.67 g (2.4 mmol) ofmethyl 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate in 20 mlof dichloromethane. After stirring for 2 h 30, water is added. Theprecipitate formed is filtered off, rinsed with water, and driedovernight at 40° C. under reduced pressure. 0.77 g of a yellow solid isobtained.

Melting point: 230° C.

MH+: 375, 377

Methyl2-amino-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate

0.248 g (1.38 mmol) of [4-(methoxycarbonyl)phenyl]boronic acid, 0.57 g(2.30 mmol) of potassium carbonate in 2 ml of water, and 0.027 g (0.02mmol) of tetrakis(triphenylphosphine)palladium are added to a solutionof 0.43 g (1.15 mmol) of methyl2-amino-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 10 mlof DME, under an inert argon atmosphere. The reaction medium is heatedat 90° C. for 2 hours. The reaction medium is acidified with a 1Naqueous solution of hydrochloric acid, and extracted withdichloromethane. The organic phase is washed with water, dried oversodium sulphate, filtered, and concentrated under reduced pressure. Thesolid obtained is dissolved in 5 ml of DMF. 30 μl (0.5 mmol) of methyliodide and 0.052 g (0.16 mmol) of caesium carbonate are added. Afterstirring for 24 hours at ambient temperature, the reaction medium ishydrolysed with water and then extracted with ethyl acetate. The organicphase is dried over sodium sulphate, filtered, and then concentratedunder reduced pressure. The solid obtained is taken up in methanol.After filtration and drying overnight at 50° C. under reduced pressure,0.379 g of a yellow powder is obtained.

Melting point: 203° C.

MH+: 430

Methyl5-({1-(3-[methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-[(propylcarbamoyl)amino]benzoate

0.181 g (0.61 mmol) of triphosgene is added, under an inert atmosphere,to 0.75 g (0.87 mmol) of methyl2-amino-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoatein 10 ml of dioxane. The reaction medium is heated at 100° C. for 3hours. 0.14 ml (1.75 mmol) of propylamine and 0.37 ml (2.62 mmol) oftriethylamine are added at ambient temperature. After stirring for 2hours at ambient temperature, the reaction medium is hydrolysed withwater. The medium is filtered, washed with water, and dried underreduced pressure at 50° C. overnight. The solid obtained is purified bysilica gel column chromatography with a dichloromethane/methanol (95/5)mixture. 0.27 g of a yellow powder is obtained.

Melting point: 212° C.

MH+: 515

3-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid

1.31 ml (1.31 mmol) of a 1N aqueous solution of sodium hydroxide areadded to 0.27 g (0.52 mmol) of methyl5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-[(propylcarbamoyl)amino]benzoatein 8 ml of methanol. The reaction medium is heated at 70° C. for 5.5hours. The methanol is concentrated under reduced pressure. The residueis taken up in water. The aqueous phase is acidified with a 1N aqueoussolution of hydrochloric acid, and then extracted with dichloromethane.The organic phase is dried over sodium sulphate, filtered, and thenconcentrated under reduced pressure. The solid obtained is taken up inmethanol and then filtered, and dried at 50° C. under reduced pressureovernight. 0.245 g of a yellow solid is obtained.

Melting point: 365° C.

MH+: 469

Sodium Salt of3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid

0.51 ml (0.51 mmol) of a 1N aqueous solution of sodium hydroxide isadded to 0.245 g (0.52 mmol) of3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid in 5 ml of methanol. The reaction medium is stirred for 1.5 hoursat ambient temperature. After the addition of diisopropyl ether, theprecipitate formed is filtered off, rinsed with diisopropyl ether, anddried at 50° C. under reduced pressure overnight. 0.242 g of a yellowpowder is obtained.

Melting point: 383° C.

MH+: 469

¹H NMR (D6-DMSO, 400 MHz):

0.90 (t, J=7.82 Hz, 3H), 1.58-1.67 (m, 2H), 3.88 (t, J=7.07 Hz, 1H),7.32-7.35 (m, 2H), 7.45 (t, J=7.82, 1H), 7.53 (t, J=7.82 Hz, 1H),7.88-7.94 (m, 2H), 8.22 (d, J=8.94 Hz, 1H), 8.44 (t, J=1.7 Hz, 1H), 8.74(d, J=8.7 Hz, 1H), 9.14 (d, J=1.9 Hz, 1H), 9.82 (d, J=7 Hz, 1H), 11.9(bs, 1H).

EXAMPLE 3 Compound No. 83-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridine-6-carboxylicacid3-[(4-Amino-3-carboxyphenyl)carbonyl]imidazo[1,5-a]pyridine-6-carboxylicacid

3.68 ml (0.026 mol) of triethylamine and then, under a nitrogenatmosphere at ambient temperature, 1.5 g (8.5 mmol) of methylimidazo[1,5-a]pyridine-6-carboxylate [described in WO 06/097625] areadded to 4.02 g (0.014 mol) of4-oxo-2-phenyl-4H-3,1-benzoxazin-6-carbonyl chloride in 60 ml of1,2-dichloroethane. After stirring for 24 hours at ambient temperature,the reaction medium is filtered, and washed with 1,2-dichloroethane,then with a 1N aqueous solution of hydrochloric acid and then withwater. After drying overnight under reduced pressure at 40° C., theproduct obtained is dissolved in 60 ml of NMP. 3.59 g (6.4 mmol) ofpotassium hydroxide dissolved in 11 ml of water are added. The reactionmedium is heated at 100° C. for 4 hours and then poured into a 1Naqueous solution of hydrochloric acid. After filtration, the solidobtained is rinsed with water and then dried overnight in an oven underreduced pressure at 40° C. 5.45 g of a yellow solid are obtained.

MH+: 326

Methyl3-{[4-amino-3-(methoxycarbonyl)phenyl]carbonyl}imidazo[1,5-a]pyridine-6-carboxylate

9.4 g (2.9 mmol) of caesium carbonate and then 1.8 ml (2.9 mmol) ofmethyl iodide, at ambient temperature are added, under an inertatmosphere, to 4.2 g (1.3 mmol) of3-[(4-amino-3-carboxyphenyl)carbonyl]imidazo[1,5-a]pyridine-6-carboxylicacid in 60 ml of DMF. After stirring for 4.5 hours at ambienttemperature, the reaction medium is hydrolysed with water. Theprecipitate obtained is filtered off, rinsed with water, and then driedat 40° C. under reduced pressure overnight. The solid obtained ispurified by silica gel column chromatography, elution being carried outwith dichloromethane. 1.3 g of a yellow solid are obtained.

MH+: 354

Methyl3-({3-(methoxycarbonyl)-4-[(propylcarbamoyl)amino]imidazo[1,5-a]pyridine-6-carboxylate

0.14 g (0.49 mmol) of triphosgene is added, at ambient temperature undera nitrogen atmosphere, to 0.3 g (0.7 mmol) of methyl3-{[4-amino-3-(methoxycarbonyl)phenyl]carbonyl}imidazo[1,5-a]pyridine-6-carboxylatein 10 ml of anhydrous dioxane. After heating for 1 h 15 at 100° C., 0.12ml (1.4 mmol) of n-propylamine and 0.29 ml (2 mmol) of triethylamine areadded to the reaction medium at ambient temperature. After stirring for4 hours at ambient temperature, the reaction medium is hydrolysed withwater. The precipitate obtained is filtered off, rinsed with water, andthen dried under reduced pressure at 40° C. overnight. The solidobtained is triturated from THF and then filtered and dried underreduced pressure at 40° C. overnight. 0.21 g of a yellow solid isobtained.

Melting point: 266° C.

MH+: 439

3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridine-6-carboxylicacid

1.2 ml (1.2 mmol) of a 1N aqueous solution of sodium hydroxide areadded, at ambient temperature, to 0.21 g of methyl3-({3-(methoxycarbonyl)-4-[(propylcarbamoyl)amino]imidazo[1,5-a]pyridine-6-carboxylatein 5 ml of methanol. After refluxing for 4 hours, the reaction medium isacidified with a 1N aqueous solution of hydrochloric acid. Theprecipitate obtained is filtered off and then rinsed with water anddried under reduced pressure at 40° C. overnight. The solid obtained isrecrystallized while hot from methanol and then dried under reducedpressure at 40° C. overnight. 0.118 g of a yellow solid is obtained.

Melting point: 384° C.

MH+: 393

¹H-NMR (D6-DMSO, 400 MHz):

0.92 (t, J=7.2 Hz, 3H), 1.59-1.68 (m, 2H), 3.87-3.94 (m, 2H), 7.33 (d,J=8.2 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H), 7.98 (s, 1H), 8.06 (d, J=9.3 Hz,1H), 8.59 (d, J=8.51 Hz, 1H), 9.20 (d, J=2.03 Hz, 1H), 11.8 (s, 1H),13.7 (s, 1H).

EXAMPLE 4 Compound No. 49 Sodium Salt of3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid Methyl2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate

2.14 g (7.2 mmol) of triphosgene are added, at ambient temperature underan inert atmosphere, to 2.58 g (6 mmol) of methyl2-amino-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoatein 50 ml of dioxane. After refluxing for 7 hours, 2.25 g (18 mmol) of4-fluorobenzylamine and 1.82 g (18 mmol) of triethylamine are added atambient temperature. The reaction medium is refluxed for 3 hours andthen concentrated under reduced pressure. The residue is triturated fromwater. After filtration, the solid is rinsed with methanol and thendried under reduced pressure at 40° C. overnight. 3.3 g of a yellowsolid are obtained.

MH+: 581

3-(3-{[3-(4-Fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid

2.85 ml (0.0285 mol) of a 1N aqueous solution of sodium hydroxide areadded to 3.3 g (5.7 mmol) of methyl2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoatedissolved in 250 ml of methanol. After refluxing for 2 hours, thereaction medium is acidified with 50 ml of a 1N aqueous solution ofhydrochloric acid and then diluted with 700 ml of water. The precipitateobtained is filtered off, and dried under reduced pressure at 40° C.overnight. 3.01 g of a yellow solid are obtained.

MH+: 535

Methyl3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate

2.44 g (7.5 mmol) of caesium carbonate and 1.06 g (7.5 mmol) of methyliodide are added, under an inert atmosphere, to 1.3 g (2.5 mmol) of3-(3-{[3-(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid in 50 ml of DMF. The reaction medium is stirred for 3 hours atambient temperature under a nitrogen atmosphere and then concentratedunder reduced pressure. The residue obtained is washed with 200 ml ofwater and then dried under reduced pressure at 40° C. overnight. 1.35 gof a yellow solid are obtained.

MH+: 563

Sodium Salt of3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid

24 ml (24 mmol) of a 1N aqueous solution of lithium hydroxide are addedto 1.3 g (2.4 mmol) of methyl3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoatein 120 ml of THF. The reaction medium is refluxed for 5 hours and thenacidified at 5° C. with 45 ml of a 1N aqueous solution of hydrochloricacid and, finally, diluted with 200 ml of water. After filtration, theresidue obtained is dried under reduced pressure at 40° C. overnight.

0.62 ml (0.62 mmol) of a 1N aqueous solution of sodium hydroxide isadded to 0.35 g (0.64 mmol) of the yellow solid obtained, in 20 ml ofmethanol. After filtration, the residue obtained is dried under reducedpressure at 40° C. overnight. 0.38 g of a yellow solid is obtained.

MH+: 549

¹H-NMR (D6-DMSO, 500 MHz):

3.62 (s, 3H), 5.17 (s, 2H), 7.11-7.18 (ps t, J=8.9 Hz, 2H), 7.35-7.40(ps t, 8.9 Hz, 1H), 7.42-7.48 (m, 3H), 7.54-7.60 (ps t, J=8.9 Hz, 1H),7.70-7.74 (ps d, J=8.9 Hz, 1H), 7.89-7.95 (ps t, J=8.9 Hz, 2H),8.26-8.30 (ps d, J=8.9 Hz, 1H), 8.44-8.48 (m, 1H), 8.96-9.01 (ps d,J=8.9 Hz, 1H), 9.22-9.24 (m, 1H), 9.88-9.91 (ps d, J=7.2 Hz, 1H).

EXAMPLE 5 Compound No. 293-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzamide

10.7 mg (0.2 mmol) of ammonium chloride, 5.17 mg (0.4 mmol) ofN,N-diisopropylethylamine and 49.2 mg (0.2 mmol) of TOTU are added, at0° C., under an inert atmosphere, to 46.8 mg (0.1 mmol) of3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid in 2 ml of DMF. The reaction medium is stirred for 12 hours atambient temperature and then poured into 30 ml of a saturated solutionof sodium hydrogen carbonate. The precipitate obtained is filtered off,washed with water, and dried under reduced pressure at 40° C. overnight.0.042 g of a yellow solid is obtained.

MH+: 468

¹H-NMR (D6-DMSO, 500 MHz):

δ=0.92 (t, 3H, J=7.7 Hz), 1.66 (tq, 2H, J=7.7 Hz, 7.3 Hz), 3.94 (t, 2H,J=7.3 Hz), 7.34-7.42 (2 m, 2H), 7.52-7.61 (2 m, 2H), 7.69 (t, 1H, J=7.6Hz), 7.96 (m, 1H), 8.10-8.23 (2 m, 2H), 8.41-8.46 (m, 2H), 8.80 (dd, 1H,J=8.9 Hz, 2.2 Hz), 9.27 (d, 1H, 1.9 Hz), 9.88 (d, 1H, J=7.1 Hz), 11.83(s, 1H).

EXAMPLE 6 Compound No. 346-({1-[3-(5-Methyl-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl-3-propylquinazoline-2,4(1H,3H)-dioneN′-Acetyl-3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzohydrazide

29.6 mg (0.4 mmol) of acetohydrazide, 98.4 mg (0.3 mmol) of TOTU and0.104 ml (0.6 mmol) of N,N-diisopropylethylamine are added, under aninert atmosphere, at 0° C., to 93.7 mg (0.2 mmol) of3-{3-[2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-yl}benzoicacid in 6 ml of DMF. The reaction medium is stirred for 1 hour at 0° C.and then for 6 hours at 50° C. and then concentrated under reducedpressure. The residue is taken up in 10 ml of methanol. The precipitateobtained is filtered off, washed with dyethyl ether and with pentane,and then dried under reduced pressure at 40° C. overnight. 45 mg of ayellow solid are obtained.

MH+: 525

6-({1-[3-(5-Methyl-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl-3-propylquinazoline-2,4(1H,3H)-dione

35 mg (0.066 mmol) ofN′-acetyl-3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzohydrazidein 1 ml of phosphorus oxychloride are heated at 100° C. for 15 minutes.The reaction medium is concentrated under reduced pressure. The residueobtained is hydrolysed with water and with a saturated solution ofsodium hydrogen carbonate. The aqueous phase is extracted withdichloromethane. The organic phase is concentrated under reducedpressure. The residue obtained is purified by silica gel columnchromatography, elution being carried out with methanol. 0.025 g of ayellow solid is obtained.

MH+: 507

¹H-NMR (D6-DMSO, 500 MHz):

0.91 (t, J=7.5 Hz, 3H), 1.65 (qt, J=7.5 Hz, 7.5 Hz, 2H), 2.67 (s, 3H),3.93 (t, J=7.5 Hz, 2H), 7.33-7.43 (m, 2H), 7.58-7.64 (m, 1H), 7.77-7.84(m, 1H), 8.04-8.06 (m, 1H), 8.28-8.32 (m, 1H), 8.39-8.43 (m, 1H), 8.59(s, 1H), 8.71-8.74 (m, 1H), 9.37 (s, 1H), 9.86-9.90 (s, 1H), 11.85 (brs, 1H).

EXAMPLE 7 Compound No. 366-({1-[3-(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-3-propylquinazoline-2,4(1H,3H)-dione

3-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}-N-[(1E)-hydroxyethanimidoyl]benzamide

39 mg (0.24 mmol) of 1,1′-carbonyldiimidazole are added, at ambienttemperature under an inert atmosphere, to 94 mg (0.2 mmol) of3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid in 5 ml of DMF. After stirring for 12 hours at ambient temperature,22.2 mg (0.3 mmol) of acetamidoxime are added. The reaction medium isstirred for 5 hours at ambient temperature and then concentrated underreduced pressure. The residue is triturated from dyethyl ether,filtered, and then dried under reduced pressure at 40° C. overnight.0.101 g of a yellow solid is obtained.

MH+: 525

6-({1-[3-(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-3-propylquinazoline-2,4(1H,3H)-dione

A solution of 0.1 g (0.19 mmol) of3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}-N-[(1E)-hydroxyethanimidoyl]benzamidein 3 ml of DMF is heated at 120° C. for 5 hours. The reaction medium isconcentrated under reduced pressure. The residue obtained is taken up indyethyl ether, filtered, and then dried under reduced pressure at 40° C.overnight. 0.083 g of a yellow solid is obtained.

MH+: 507

¹H-NMR (D6-DMSO):

0.91 (t, J=7.5 Hz, 3H), 1.65 (qt, J=7.5 Hz, 7.5 Hz, 2H), 2.47 (s, 3H),3.94 (t, J=7.5 Hz, 2H), 7.36-7.45 (m, 2H), 7.59-7.66 (m, 1H), 7.82-7.89(m, 1H), 8.13-8.19 (m, 1H), 8.36-8.45 (m, 2H), 8.68 (s, 1H), 8.75-8.79(m, 1H), 9.25. 9.28 (m, 1H), 9.85-9.90 (m, 1H), 11.85 (br s, 1H).

EXAMPLE 8 Compound No. 13N-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}methanesulphonamideMethyl5-[(1-bromoimidazo(1,5-a)pyridin-3-yl)carbonyl]-2-[(propylcarbamoyl)aminobenzoate

0.55 g (0.0019 mol) of triphosgene is added, at ambient temperatureunder an inert atmosphere, to 1 g (2.7 mmol) of methyl2-amino-5-[1-bromo(imidazo[1,5-a]pyridin-3-yl)carbonyl)]benzoate in 30ml of anhydrous dioxane. The reaction medium is heated for 1.5 hours at100° C. 0.44 ml (5.3 mmol) of n-propylamine and 1.12 ml (8 mmol) oftriethylamine are added at ambient temperature. After 2 h 30, thereaction medium is hydrolysed with water. The aqueous phase is extractedwith dichloromethane. The organic phase is dried over sodium sulphate,filtered, and then concentrated under reduced pressure. The solidobtained is triturated from dichloromethane, filtered, and then driedunder reduced pressure at 40° C. overnight.

MH+: 459, 461

Melting point: 236° C.

6-[(1-Bromoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-2,4(1H,3H)-dione

3.14 ml (3.1 mmol) of a 1N aqueous solution of sodium hydroxide areadded, at ambient temperature, to 1.2 g (2.6 mmol) of methyl5-[(1-bromoimidazo(1,5-a)pyridin-3-yl)carbonyl]-2-[(propylcarbamoyl)aminobenzoatein 20 ml of methanol. After refluxing for 3 hours, the reaction mediumis hydrolysed with a 1N aqueous solution of hydrochloric acid. Theprecipitate obtained is filtered off, rinsed with methanol, and thendried under reduced pressure at 40° C. overnight. 1.09 g of a yellowsolid are obtained.

MH+: 427, 429

Melting point: 322° C.

6-[(1-Aminoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-2,4(1H,3H)-dione

1.45 g (4.7 mmol) of caesium carbonate, 1.13 ml (6.7 mmol) ofbenzophenoneimine, 0.278 g (0.45 mmol) of binap and 0.204 g (0.22 mmol)of dibenzylideneacetone dipalladium are added, at ambient temperatureunder an argon atmosphere, to 0.955 g (2 mmol) of6-[(1-bromoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-2,4(1H,3H)-dionein 20 ml of DMSO. The reaction medium is heated at 110° C. for 18 hours.The reaction medium is extracted with ethyl acetate. The organic phaseis dried over sodium sulphate, filtered and concentrated under reducedpressure.

The residue obtained is dissolved in 40 ml of THF. 4.5 ml (9 mmol) of a2N aqueous solution of hydrochloric acid are added at ambienttemperature. After stirring for 4 hours at ambient temperature, thereaction medium is concentrated under reduced pressure. The residueobtained is washed with dichloromethane and with methanol, and thendried under reduced pressure at 40° C. overnight. 0.558 g of a red solidis obtained.

MH+: 364

N-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}methanesulphonamide

0.1 ml (1.2 mmol) of mesyl chloride is added, at 0° C. under an inertatmosphere, to 0.25 g (0.4 mmol) of6-[(1-aminoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-2,4(1H,3H)-dionein 5 ml of pyridine. After the addition of methanol, the reaction mediumis concentrated under reduced pressure. The residue is taken up withdichloromethane. The organic phase is washed with a 1N aqueous solutionof hydrochloric acid and then with water, dried over sodium sulphate,filtered, and concentrated under reduced pressure. The residue isrecrystallized while hot from methanol, purified on a silica gel frit,elution being carried out with DMF. 0.057 g of an orange solid isobtained.

Melting point: 334° C.

MH+: 442

¹H-NMR (D6-DMSO, 400 MHz):

0.88 (t, J=7.37 Hz, 3H), 1.55-1.65 (m, 2H), 3.29 (s, 3H), 3.87-3.90 (m,2H), 7.27-7.31 (m, 2H), 7.40-7.44 (m, 1H), 7.92 (d, J=9 Hz, 1H), 8.52(d, J=8.46 Hz, 1H), 9.15 (d, J=2.18 Hz, 1H), 9.71 (d, J=7.1 Hz, 1H),10.2 (s, 1H), 11.8 (s, 1H).

EXAMPLE 9 Compound No. 82 2-Morpholin-4-yl-ethyl3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoatehydrochloride

0.022 g (0.61 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and0.189 g (1.37 mmol) of potassium carbonate are added, under an inertatmosphere, to 0.3 g (0.55 mmol) of3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid in 8 ml of DMF. After stirring for 18 h at ambient temperature andthen for 8 hours at 50° C., the reaction medium is hydrolysed withwater, and extracted with ethyl acetate. The organic phase is washedwith water, dried over sodium sulphate, filtered, and then concentratedunder reduced pressure. The yellow solid obtained is purified by silicagel column chromatography, elution being carried out with adichloromethane/methanol (95/5) mixture. 0.61 ml of a 1N aqueoussolution of hydrochloric acid is added to 0.334 g of the yellow solidobtained, in 5 ml of methanol. The reaction medium is stirred for 1 hourat ambient temperature. Dyethyl ether is added and then the reactionmedium is filtered. The precipitate obtained is rinsed with dyethylether and then dried under reduced pressure at 50° C. overnight. 0.298 gof a yellow solid is obtained.

Melting point: 215° C.

MH+: 662

¹H-NMR (D6-DMSO, 500 MHz):

3.21-3.31 (m, 2H), 3.31 (s, 3H), 3.46-3.54 (m, 2H), 3.6-3.7 (m, 2H),3.61 (s, 3H), 3.70-3.80 (m, 2H), 3.90-4 (m, 2H), 4.65-4.75 (m, 2H), 5.16(s, 2H), 7.11-7.16 (m, 2H), 7.37-7.39 (m, 1H), 7.42-7.45 (m, 2H),7.55-7.58 (m, 1H), 7.67 (d, J=9.28 Hz, 1H), 7.73 (t, J=7.69 Hz, 1H),8.07 (d, J=7.69 Hz, 1H), 8.29-8.34 (m, 2H), 8.55 (s, 1H), 8.82 (d,J=9.01 Hz, 1H), 9.27 (d, J=1.85 Hz, 1H), 9.83 (d, J=7.16 Hz, 1H), 10.9(s, 1H).

EXAMPLE 10 Compound No. 117N-[2-(Dimethylamino)ethyl]-3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzamidehydrochloride

0.06 ml (0.55 mmol) of N,N-dimethylethylenediamine, 0.134 g (0.41 mmol)of TOTU and 0.14 ml (0.82 mmol) of diisopropylethylamine are added to0.15 g (0.27 mmol) of3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid in 5 ml of DMF. The reaction medium is heated at 80° C. for 16hours. The reaction medium is hydrolysed with water, and extracted withethyl acetate. The organic phase is washed with water, dried over sodiumsulphate, filtered, and concentrated under reduced pressure. The yellowsolid obtained is purified by silica gel column chromatography, elutionbeing carried out with a dichloromethane/methanol (95/5) mixture. 0.23ml of a 1N solution of hydrochloric acid in dyethyl ether is added to0.095 g of the yellow solid obtained. After stirring for 1 hour, dyethylether is added. The precipitate obtained is filtered off, rinsed withwater, and then dried under reduced pressure at 50° C. overnight. 0.1 gof a yellow solid is obtained.

Melting point: 247° C.

MH+: 619

¹H-NMR (D6-DMSO, 400 MHz):

2.50 (m, 6H), 2.84 (s, 2H), 3.31 (s, 3H), 3.61 (s, 1H), 3.64-6.70 (m,1H), 5.16 (s, 2H), 7.7.11-7.17 (m, 2H), 7.37-7.46 (m, 3H), 7.55-7.60 (m,1H), 7.67-7.71 (m, 2H), 7.93 (d, J=8.19 Hz, 1H), 8.19 (d, J=7.51 Hz,1H), 8.38-8.43 (m, 2H), 8.87 (d, J=8.88 Hz, 1H), 8.92 (t, J=5.12 Hz,1H), 9.27 (d, J=2Hz, 1H), 9.81 (s, 1H), 9.84 (d, J=7.1 Hz, 1H).

EXAMPLE 11 Compound No. 72 Sodium Salt of3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid Propyl3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate

1.371 g (4.21 mmol) of caesium carbonate and 0.715 g (4.21 mmol) ofpropyl iodide are added, under an inert atmosphere, to 0.75 g (1.4 mmol)of3-(3-{[3-(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid in 30 ml of DMF. The reaction medium is stirred for 3 hours atambient temperature under a nitrogen atmosphere, and then concentratedunder reduced pressure. The residue obtained is washed with 100 ml ofwater and then dried under reduced pressure at 40° C. overnight. Thesolid obtained is purified by silica gel column chromatography, elutionbeing carried out with a dichloromethane/methanol (75/1) mixture. 0.55 gof a yellow solid is obtained.

MH+: 619

Sodium Salt of3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoicacid

8.9 ml (8.9 mmol) of a 1N aqueous solution of lithium hydroxide areadded to 0.55 g (0.889 mmol) of propyl3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-yl)benzoatein 50 ml of THF. The reaction medium is refluxed for 6 hours and thenacidified at 5° C. with 17 ml of a 1N aqueous solution of hydrochloricacid and, finally, diluted with 100 ml of water. After filtration, theresidue obtained is dried under reduced pressure at 40° C. overnight.

0.408 ml (0.408 mmol) of a 1N aqueous solution of sodium hydroxide isadded to 0.24 g (0.416 mmol) of the yellow solid obtained, in 20 ml ofmethanol. After filtration, the residue obtained is dried under reducedpressure at 40° C. overnight. 0.24 g of a yellow solid is obtained.

MH+: 577

1H-NMR (D6-DMSO, 500 MHz):

0.97 (t, J=7.5 Hz, 3H, 1.71 (tq, J₁/J₂=7.5 Hz, 2H), 4.18 (t, J=7.5 Hz,2H), 5.20 (s, 2H), 7.17 (ps t, J=9.3 Hz, 2H), 7.37-7.41 (m, 1H),7.44-7.49 (3 m, 3H), 7.59 (m, 1H), 7.78 (ps d, J=8.5 Hz, 1H), 7.91 (2 m,2H), 8.28 (ps d, J=9.8 Hz, 1H), 8.45 (m, 1H), 8.99-9.02 (m, 1H), 9.23(m, 1H), 9.90 (ps d, J=7.5 Hz, 1H).

EXAMPLE 12 Compound No. 1133-(4-Fluorobenzyl)-1-methyl-6-[(1-pyridin-3-ylimidazo[1,5-a]pyridin-3-yl)carbonyl]quinazoline-2,4(1H,3H)-dioneMethyl5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-{[(4-fluorobenzyl)carbamoyl]amino}benzoate

3 g (10.4 mmol) of triphosgene diluted in 40 ml of dioxane are added to5.57 g (14.9 mmol) of methyl2-amino-5-[1-bromo(imidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 160ml of dioxane, under an inert atmosphere. The reaction medium isrefluxed for 1 hour. 3.7 g (0.030 mol) of 4-fluorobenzylamine and 6.22ml (0.045 mol) of triethylamine are added at ambient temperature. Thereaction medium is stirred for 4 hours at ambient temperature and thenhydrolysed with water. The precipitate obtained is filtered off, rinsedwith water, and dried under reduced pressure at 50° C. overnight. Thesolid obtained is taken up with methanol, filtered, rinsed withmethanol, and dried under reduced pressure overnight. 12 g of a yellowsolid are obtained (yield=95.5%).

MH+: 525, 527

Melting point: 203° C.

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

22.33 ml (22.33 mmol) of a 1N aqueous solution of sodium hydroxide areadded to 7.8 g (0.0149 mol) of methyl5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-{[(4-fluorobenzyl)carbamoyl]amino}benzoatein 100 ml of methanol. The reaction medium is refluxed for 2.5 hours.After hydrolysis with water, the precipitate obtained is filtered off,rinsed with water, and dried under reduced pressure at 50° C. overnight.

The solid obtained is taken up in a 0.1N aqueous solution ofhydrochloric acid, filtered, rinsed with water, and dried under reducedpressure at 50° C. overnight. 5.4 g of a yellow solid are obtained.

Melting point: 325° C.

MH+: 494, 496

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1-methylquinazoline-2,4(1H,3H)-dione

1.87 g (5.7 mmol) of caesium carbonate and 0.39 ml (6.2 mmol) of methyliodide are added, at anbient temperature under an inert atmosphere, to2.6 g (5.17 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)quinazoline-2,4(1H,3H)-dionein 50 ml of anhydrous DMF. The reaction medium is stirred for 18 hoursat ambient temperature and then filtered. The precipitate is rinsed withwater and then dried under reduced pressure at 50° C. overnight. 2.54 gof a yellow solid are obtained.

Melting point: 280° C.

MH+: 507, 509

3-(4-Fluorobenzyl)-1-methyl-6-[(1-pyridin-3-ylimidazo[1,5-a]pyridin-3-yl)carbonyl]quinazoline-2,4(1H,3H)-dione

0.04 g (0.32 mmol) of 3-pyridylboronic acid, 0.2 g (0.81 mmol) ofpotassium phosphate dihydrate dissolved in 0.29 ml of water, and 6.2 mg(0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.15 g(0.27 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1-methylquinazoline-2,4(1H,3H)-dionein 3 ml of DMF under an inert argon atmosphere. The reaction medium ismicrowave-heated at 150° C. for 20 minutes. After filtration over talc,the reaction medium is concentrated under reduced pressure. The residueobtained is purified by silica gel column chromatography, elution beingcarried out with a dichloromethane/methanol (95/5) mixture. 0.12 g of ayellow solid is obtained.

Melting point: 207° C.

MH+: 506

3-(4-Fluorobenzyl)-1-methyl-6-[(1-pyridin-3-ylimidazo[1,5-a]pyridin-3-yl)carbonyl]quinazoline-2,4(1H,3H)-dionehydrochloride

0.35 ml (0.35 mmol) of a 1N solution of hydrochloric acid in dyethylether is added to 0.12 g (0.23 mmol) of3-(4-fluorobenzyl)-1-methyl-6-[(1-pyridin-3-ylimidazo[1,5-a]pyridin-3-yl)carbonyl]quinazoline-2,4(1H,3H)-dionein 3 ml of methanol. After stirring for 1 hour at ambient temperature,the reaction medium is filtered. The precipitate obtained is rinsed withdyethyl ether, and dried under reduced pressure at 50° C. overnight.0.12 g of a yellow solid is obtained.

MH+: 506

Melting point: 267° C.

¹H-NMR (D6-DMSO, 400 MHz):

3.60 (s, 3H), 5.16 (s, 2H), 7.14 (t, J=8.34 Hz, 2H), 7.36-7.47 (m, 3H),7.60 (t, J=7.05 Hz, 1H), 7.65 (d, J=8.98 Hz, 1H), 7.83 (t, J=7.05 Hz,1H), 8.43 (d, J=8.98 Hz, 1H), 8.66-8.75 (m, 2H), 8.83 (d, J=8.98 Hz,1H), 9.30 (m, 2H), 9.81 (d, J=7.05 Hz, 1H).

EXAMPLE 13 Compound No. 533-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid 2-Amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid

60 ml (60 mmol) of a 1N aqueous solution of sodium hydroxide are added,at ambient temperature, to 3.74 g (10 mmol) of methyl2-amino-5-[1-bromo(imidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 300ml of methanol and 125 ml of water. The reaction medium is refluxed for6 hours and then 140 ml of a 1N aqueous solution of hydrochloric acidare added. After concentration of the methanol under reduced pressure,the precipitate obtained is filtered off, washed with water, and thendried under reduced pressure at 40° C. for 18 hours. 3.53 g of a yellowsolid are obtained.

MH+: 360, 362

2-(Acetylamino)-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]benzoicacid

0.92 g (2.56 mmol) of2-amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid in 30ml of acetic anhydride are refluxed for 5.5 hours. The reaction mediumis concentrated under reduced pressure. The residue is taken up in waterand then filtered and dried under reduced pressure overnight at 40° C.1.1 g of a yellow solid are obtained.

MH+: 402, 404

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-methyl-3-propylquinazolin-4(3H)-one

1.32 g (22.4 mmol) of n-propylamine are added, at 0° C. under an inertatmosphere, to 0.9 g (2.2 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-methyl-4H-3,1-benzoxazin-4-onein 15 ml of glacial acetic acid. The reaction medium is microwave-heatedfor 45 minutes at 160° C. The reaction medium is concentrated underreduced pressure. The residue obtained is taken up with a saturatedaqueous solution of sodium carbonate. The precipitate obtained isfiltered off and then dried under reduced pressure at 50° C. overnight.0.67 g of a yellow solid is obtained.

MH+: 425, 427

Methyl3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoate

0.35 g (1.95 mmol) of 3-methoxycarbonylphenylboronic acid, 0.689 g (3.24mmol) of potassium phosphate dissolved in 3 ml of water, and 0.037 g(0.032 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.69g (1.62 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-methyl-3-propylquinazolin-4(3H)-onein 15 ml of NMP. The reaction medium is microwave-heated for 15 minutesat 150° C. and then concentrated under reduced pressure. After theaddition of 100 ml of water, the precipitate is filtered off and thendried under reduced pressure at 50° C. overnight. The solid obtained ispurified by silica gel column chromatography, elution being carried outwith a dichloromethane/methanol (50/1) mixture.

MH+: 481

3-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid

7.65 ml of a 1N aqueous solution of sodium hydroxide are added to 0.735g (1.53 mmol) of methyl3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoatein 30 ml of THF. The reaction medium is refluxed for 2.5 hours. Afteracidification with 10 ml of a 1N aqueous solution of hydrochloric acid,the reaction medium is concentrated under reduced pressure. The residueis taken up in 20 ml of water. The precipitate obtained is filtered off,and dried under reduced pressure at 50° C. overnight. 0.52 g of a yellowsolid is obtained.

MH+: 467

¹H-NMR (D6-DMSO, 500 MHz):

0.97 (t, J=7.6 Hz, 3H), 1.69-1.76 (m, 2H), 2.71 (s, 3H), 4.07-4.11 (m,2H), 7.40-7.44 (m, 1H), 7.59-7.66 (m, 1H), 7.71-7.80 (m, 2H), 8.01-8.05(m, 1H), 8.28-8.39 (2 m, 2H), 8.55-8.58 (m, 1H), 8.79-8.82 (m, 1H),9.30-9.34 (m, 1H), 9.88-9.22 (m, 1H), 13.23 (br s, 1H).

EXAMPLE 14 Compound No. 553-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzamide

0.107 g (2 mmol) of ammonium chloride, 0.328 g (1 mmol) of TOTU and0.517 g (4 mmol) of N,N-diisopropylethylamine are added, at ambienttemperature under an inert atmosphere, to 0.233 g (0.5 mol) of3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoicacid in 30 ml of DMF. The reaction medium is stirred for 5 hours atambient temperature and then concentrated under reduced pressure. 50 mlof a saturated solution of sodium hydrogen carbonate are added to theresidue. The precipitate obtained is filtered off, and then dried underreduced pressure at 50° C. overnight. 0.230 g of a yellow solid isobtained.

MH+: 466

¹H-NMR (D6-DMSO, 500 MHz):

0.98 (t, J=8 Hz, 3H), 1.74 (m, 2H), 2.71 (s, 3H), 4.10 (t, J=8.1 Hz,2H), 7.40-7,45 (m, 1H), 7.54-7.64 (m, 2H), 7.67-7.71 (m, 1H), 7.75-7.80(m, 1H), 7.96-8.00 (m, 1H), 8.19-8.23 (m, 2H), 8.42-8.48 (m, 2H),8.82-8.85 (m, 1H), 9.39-9.41 (m, 1H), 9.90-9.95 (m, 1H).

EXAMPLE 15 Compound No. 36-(Imidazo[1,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3H)-one

0.36 g (3.6 mmol) of formamidine acetate is added to 0.2 g (0.72 mmol)of 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid (describedin WO 06/097625) in 7 ml of ethanol. The reaction medium ismicrowave-heated at 150° C. for 25 minutes. The reaction medium ishydrolysed with a 1N aqueous solution of sodium hydroxide. The aqueousphase is extracted with dichloromethane. The heterogeneous organic phaseis filtered. The solid obtained is purified by silica gel columnchromatography, elution being carried out with adichloromethane/methanol (90/10) mixture. 54 mg of a yellow solid areobtained.

MH+: 291

Melting point: 289° C.

¹H-NMR (D6-DMSO, 400 MHz):

7.29-7.47 (m, 2H), 7.80-7.82 (m, 1H), 7.96 (s, 1H), 8.04-8.07 (m, 1H),8.23 (s, 1H), 8.67-8.70 (m, 1H), 9.29 (s, 1H), 9.52-9.53 (m, 1H), 12.5(s, 1H).

EXAMPLE 16 Compound No. 177N,N-1,2-Tetramethyl-4-oxo-6-{[1-(pyridin-3-yl)imidazo[1,5-a]pyridin-3-yl]carbonyl}-1,4-dihydroquinoline-3-carboxamide6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2H-3,1-benzoxazine-2,4(1H)-dione

1.30 g (4.37 mmol) of triphosgene dissolved in 10 ml of dioxane areadded, under an inert atmosphere at ambient temperature, to 1.05 g (2.91mmol) of 2-amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoicacid. The reaction medium is refluxed for 4 hours, and then concentratedunder reduced pressure. 100 ml of water are added to the residue. Theprecipitate obtained is filtered off under reduced pressure at 40° C.for 18 hours. 1.1 g of a yellow solid are obtained.

MH+: 386, 388

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

808 mg (5.7 mmol) of methyl iodide and 164 mg (3.42 mmol) of 50% sodiumhydride are added, at ambient temperature under an inert atmosphere, to1.1 g (2.85 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2H-3,1-benzoxazine-2,4(1H)-dionein 20 ml of DMF. After stirring for 3 hours, the reaction medium ispoured into 200 ml of ice-cold water. The precipitate is filtered off,rinsed with water, and then dried under reduced pressure for 18 hours at40° C. 1.13 g of a yellow solid are obtained.

MH+: 402, 403.95

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-N,N-1,2-tetramethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

1.25 ml of a 2N aqueous solution of sodium hydroxide are added, atambient temperature, to 333 mg (2.5 mmol) of N,N-dimethylacetoacetamidein 3 ml of DMF. After stirring for 1 hour, 400 mg (1 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dionedissolved in 25 ml of DMF are added. The reaction medium is heated for 6hours at 50° C. under an inert atmosphere. The reaction medium isconcentrated under reduced pressure. The residue obtained is purified bysilica gel column chromatography, elution being carried out with adichloromethane/methanol 20/1 mixture. 220 mg of a yellow oil areobtained.

MH+: 467, 469

N,N-1,2-Tetramethyl-4-oxo-6-{[1-(pyridin-3-yl)imidazo[1,5-a]pyridin-3-yl]carbonyl}-1,4-dihydroquinoline-3-carboxamide

115 mg (0.37 mmol) of 3-pyridinylboronic acid, 331 mg (1.56 mmol) ofpotassium phosphate dissolved in 1 ml of water, and 18 mg (15.6 μmol) oftetrakis(triphenylphosphine)palladium are added, at ambient temperatureunder an inert atmosphere, to 365 mg (0.78 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-N,N-1,2-tetramethyl-4-oxo-1,4-dihydroquinoline-3-carboxamidein 20 ml of N-methylpyrolidone. The reaction medium is microwave-heatedat 150° C. for 25 minutes and then concentrated under reduced pressure.The residue obtained is purified by silica gel column chromatography,elution being carried out with a dichloromethane/methanol 9/1 mixture.0.290 g of a yellow oil is obtained.

MH+: 466

¹H-NMR (D6-DMSO, 500 MHz):

2.44 (s, 3H), 2.89 (s, 3H), 3.03 (s, 3H), 3.89 (s, 3H), 7.39-7.43 (m,1H), 7.59-7.64 (2 m, 2H), 8.07 (d, J=9.7 Hz, 1H), 8.44-8.49 (2 m, 2H),8.67 (d, J=4.8 Hz, 1H), 8.86 (dd, J=9.7 Hz and 2.2 Hz, 1H), 9.32-9.34(m, 1H), 9.55 (d, J=2.2 Hz, 1H), 9.93 (d, J=7.4 Hz, 1H).

EXAMPLE 17 Compound No. 223 Sodium Salt of3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoicacid Methyl5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-({[2-(4-fluorophenoxy)ethyl]carbamoyl}amino)benzoate

4.75 g (16 mmol) of triphosgene are added, at ambient temperature underan inert atmosphere, to 4.99 g (13.33 mmol) of methyl2-amino-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoatein 220 ml of dioxane. After refluxing for 5 hours, 6.21 g (40 mmol) of2-(4-fluorophenoxy)-1-ethylamine and 4.05 g (40 mmol) of triethylamineare added at ambient temperature. The reaction medium is refluxed for 3hours and then concentrated under reduced pressure. The residue istriturated from water. After filtration, the solid is rinsed withmethanol and then dried under reduced pressure at 40° C. overnight. 6.67g of a yellow solid are obtained.

MH+: 555

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]quinazoline-2,4(1H,3H)-dione

60.1 ml (60.1 mmol) of a 1N aqueous solution of sodium hydroxide areadded to 6.67 g (12 mmol) of methyl5[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-({[2-(4-fluorophenoxy)ethyl]carbamoyl}amino)benzoatedissolved in 600 ml of methanol. After refluxing for 2 hours, thereaction medium is acidified with 120 ml of a 1N aqueous solution ofhydrochloric acid and then diluted with 2000 ml of water. Theprecipitate obtained is filtered off, and dried under reduced pressureat 40° C. overnight. 5.83 g of a yellow solid are obtained.

MH+: 523.2, 525.2

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1H,3H)-dione

7.22 g (22.16 mmol) of caesium carbonate and 5.65 g (33.24 mmol) ofpropyl iodide are added, under an inert atmosphere, to 5.6 g (11.08mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]quinazoline-2,4(1H,3H)-dionein 300 ml of DMF. The reaction medium is stirred for 12 hours at ambienttemperature under a nitrogen atmosphere and then concentrated underreduced pressure. The residue obtained is washed with 700 ml of waterand then dried under reduced pressure at 40° C. overnight. 5.74 g of ayellow solid are obtained.

MH+: 565, 567

Methyl3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoate

2.178 g (12.1 mmol) of 3-methoxycarbonylphenylboronic acid, 4.279 g(20.16 mmol) of potassium phosphate dissolved in 30 ml of water, and582.4 g (0.504 mmol) of tetrakis(triphenylphosphine)palladium are addedto 5.7 g (10.08 mmol) of6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1H,3H)-dionein 180 ml of NMP. The reaction medium is microwave-heated for 15 minutesat 120° C. and then concentrated under reduced pressure. The solidobtained is purified by silica gel column chromatography, elution beingcarried out with a dichloromethane/methanol (100/1) mixture. 4.32 g of ayellow solid are obtained.

MH+: 621.3

Sodium Salt of3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoicacid

69.6 ml (69.6 mmol) of a 1N aqueous solution of lithium hydroxide areadded to 4.32 g (6.96 mmol) of methyl3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoatein 500 ml of THF. The reaction medium is refluxed for 3 hours and thenacidified at ambient temperature with 150 ml of a 1N aqueous solution ofhydrochloric acid and, finally, diluted with 700 ml of water. Afterfiltration, the residue obtained is dried under reduced pressure at 40°C. overnight.

5.88 ml (5.88 mmol) of a 1N aqueous solution of sodium hydroxide areadded to 4.11 g (6 mmol) of the yellow solid obtained, in 100 ml ofmethanol. After filtration, the residue obtained is dried under reducedpressure at 40° C. overnight. 3.46 g of a yellow solid are obtained.

MH+: 607.3

Mp: 190-205° C. (decomposition)

1H-NMR (D6-DMSO, 500 MHz):

0.98 (t, J=7.7 Hz, 3H), 1.71 (tq, J1=J2=7.7 Hz, 2H), 4.17 (t, J=7.7 Hz,2H), 4.24 (t, J=6.6 Hz, 2H), 4.39 (t, J=6.6 Hz, 2H), 6.97-7.00 (2 m,2H), 7.10-7.16 (2 m, 2H), 7.38-7.41 (m, 1H), 7.47-7.52 (m, 1H),7.57-7.61 (m, 1H), 7.75-7.79 (m, 1H), 7.94-7.98 (2 m, 2H), 8.26-8.30 (m,1H), 8.49-8.52 (m, 1H), 8.97-9.02 (m, 1H), 9.26-9.28 (m, 1H), 9.89-9.93(m, 1H).

The table which follows illustrates the chemical structures and thephysical properties of some compounds according to the invention. Inthis table:

-   -   Me and Et represent, respectively, methyl and ethyl groups;    -   the wavy lines indicate the bond attached to the rest of the        molecule;    -   “Mp” represents the melting point of the compound, expressed in        degrees Celsius;    -   “M+H⁺” represents the mass of the compound, obtained by LC-MS        (Liquid Chromatography-Mass Spectroscopy).

TABLE (I)

No. R₁

R₄ Salt Mp (° C.) M + H⁺  1 H

H / 304 349  2 H

H / 341 307  3 H

H / 289 291  4 H

7-COOH / 380 393  5 H

7-COOH / 404 365  7 —CO—NH₂

H / / 392  8 H

6-COOH / 384 393  9 H

HCl 234 503  10

H Na 383 469  11 H

H Na 398 365  12 H

/ 278 436  13 —NH—SO₂Me

H / 334 442  14

H Na >41 441  15

H Na >410 469  16

H / 257 497  17

H / 361 455  18

H Na 345 440  19

H Na 340 517  20

H Na 363 469  21

H Na 318 487  22

H Na 390 487  23 H

H / 308 379  24

H / 318 425  26 H

H / 263 377  28

H / 271 483  29

H / 345-346 468  30

H / 371 523  31

H Na 317 535  32

H Na 316 553  33

H Na 325 551  34

H / / 507  35

H / 294-296 450  36

H / 276-277 507  37

H / 250-260 546  38

H / 269 484  39

H / 387 509  40

H / 184-185 483  41

H / 255 498  42

H / 341 516  43

H / 268 513  44

H / 340 552  45

H / 319 534  46 H

H / / 409  47

H / 230 464  48

H / 274 440  49

H Na 182 549  50

H / 300-301 567  51

H / 290 566  52

H / 305 548  53

H / 305 467  54

H / 265 482  55

H / 238 466  56

H / 311-312 453  57

H / 251 452  58

H / 338 550  59

H / 241 521  60

H / 295 531  61

H / 255 521  62

H / 298 530  63

H / 250 511  64

H / 285 548  65

H / 231 510  66

H / 271 523  67

H / 254 522  68

H / 310 564  69

H / 319 591  70

H Na 255 564  71

H Na 284-286 579  72

H Na 239-245 577  73

H / 258 605  74

H / 250-252 576  75

H / 297-298 578  76

H / 150-153 481  77

H / 140-145 480  78

H / 263 563  79

H / 203-204 577  80

H / 141-143 494  81

H Na 226-230 494  82

H Na 215 662  83

H / 238 620  84

H Na 235-238 493  85

H Na 244-246 563  86

H / 210 646  87

H / 234 593  88

H / 266-268 587  89

H Na 275-278 549  90

H Na 222-225 606  91

H / / 517  92

H / / 442  93

H / / 472  94

H HCl / 602  95

H / / 497  95a

H HCl / 554  96

H HCl / 575  97

H HCl / 575  98

H / / 511  99

H HCl / 583 100

H / / 521 101

H / / 524 102

H / / 521 103

H / / 538 104

H HCl / 568 105

H / / 512 106

H / / 523 107

H HCl / 550 108

H / 318 562 109

H / / 548 110

H HCl 177 690 111

H HCl 187 674 112

H / 224 505 113

H HCl 267 506 114

H / 106 637 115

H / / 530 116

H HCl 214 661 117

H HCl 247 619 118

H Na / 598 119

H Na / 617 120

H Na / 593 121a

H / 259 576 121

H HCl 247 606 122

H HCl 287 592 123

H HCl 274 634 124

H / 216 521 125

H Na 258 561 126

H Na 240 589 127

H HCl 275 534 128

H HCl 273 534 129

H / 223 550 130

H Na 246 573 131

H Na 256 591 132

H HCl 291 550 133

H Na / 632 134

H / / 624 135

H / / 605 136

H Na 236 627 137

H / 112 681 138

H Na 237 599 139

H HCl 226 563 140

H / / 573 141

H / / 587 142

H Na / 667 143

H Na / 646 144

H Na / 648 145

H / / 603 146

H HCl 250 440 147

H HCl 278 468 148

H / 294 522 149

H Na 256 563 150

H HCl 225 516 151

H / 257 536 152

H / 259 549 153

H / 128 532 154

H / 233 537 155

H HCl 128 564 156

H / / 504 157

H / 278 521 158 Me

H / / 471 159

H Na 221 591 160

H HCl 525 548 161

H / 250 564 162

H HCl 230 536 163

H / 194 509 164

H / 160 618 165

H / / 617 166

H / / 482 167

H / / 587 168

H / / 506 169

H / / 522 170

H / / 630 171 Me

H / / 443 172

H Na / 525 173

H / / 524 174

H / 261 590 175

H / / 498 176

H / / 524 177

H / / 466 178

H Na / 604 179

H Na 236 591 180

H HCl 229 530 181

H Na 270 563 182

H HCl 261 502 183

H / / 506 184

H / / 524 185

H / 261 590 186

H HCl 261 502 187

H Na 238 573 188

H Na 274 545 189

H / / 498 190

H / / 524 191

H Na / 604 192

H Na 236 591 193

H HCl 229 530 194

H HCl 198 520 195

H Na 270 563 196

H HCl 218 548 197

H Na 233 591 198

H Na / 587 199

H Na 257 545 200

H Na 285 575 201

H HCl 264 560 202

H Na 258 603 203

H / / 509 204

H / / 494 205

H Na / 537 206

H / / 510 207

H Na / 565 208

H / / 510 209

H Na / 553 210

H HCl 195 506 211

H / 240 588 212

H / / 494 213

H Na / 537 214

H / / 522 215

H Na / 565 216

H / / 536 217

H / / 564 218

H / 243 511 219

H / 255 535 220 nBu

H / / 485 221

H / / 580 222

H / / 508 223

H Na / 607 224

H / / 536 225

H Na / 645 226

H Na / 579 227

H Na 313 595 228 H

H / / 429 229

H / 146 549 230

H / 227 575 231

H / / 573 232

H / / 601 233

H HCl 290 556 234

H / / 578 235

H / / 591 236

H / / 563 237

H Na 217 607 238

H / 182 591 239

H / 108 619 240

H / / 526 241

H / / 554 242

H / 285 550 243

H / / 625 244

H / / 617 245

H / / 589 246

H Na 342 527 247

H / / 566 248

H Na 349 501 249

H HCl / 592 250

H HCl / 495 251

H HCl / 551 252

H HCl / 520 253

H HCl / 495 254

H HCl / 561 255

H HCl / 589 256

H HCl / 602 257

H HCl / 549 258

H HCl / 565 259

H HCl / 539 260

H HCl / 553 261

H HCl / 541 262

H HCl / 571 263

H HCl / 545 264

H HCl / 544 265

H HCl / 590 266

H HCl / 591 267

H HCl / 557 268

H HCl / 567 269

H HCl / 541 270

H HCl / 549 271

H HCl / 589 272

H HCl / 638 273

H HCl / 545 274

H HCl / 556 275

H HCl / 632 276

H HCl / 509 277

H HCl / 555 278

H HCl / 556 279

H HCl / 573 280

H HCl / 598 281

H HCl / 567 282

H HCl / 571 283

H HCl / 522 284

H HCl / 522 285

H HCl / 550 286

H HCl / 522 287

H HCl / 563 288

H HCl / 553 289

H HCl / 563 290

H / / 395 291

H / / 510 292

H / / 538 293

H / / 466 294

H Na / 579 295

H Na / 551

The compounds according to the invention were the subject ofpharmacological assays for determining their FGF-inhibiting effect.

EXAMPLE 18 FGF-2-Induced In Vitro Angiogenesis of HUVEC Cells

In order to demonstrate the ability of the FGF-R antagonists of thepresent invention to inhibit FGF-induced angiogenesis, in vitroangiogenesis experiments were carried out with human endothelial cellsof HUVEC type stimulated with FGF-2 or b-FGF.

To do this, matrices composed of matrigel (growth factor reducedmatrigel, Becton Dickinson 356230) and collagen (rat tail collagen typeI, Becton Dickinson 354236) are deposited, at a rate of 160 μl, intoeach chamberslide well (Biocoat Cellware collagen, Type I, 8-wellculturesides: Becton Dickinson 354630), or 60 μl per well of 96-wellplates (Biocoat collagen I cellware, Becton Dickinson 354407). Thematrix is prepared by mixing ⅓ of matrigel, 1 mg/ml final concentrationof collagen, 0.1N NaOH (0.026× the volume of collagen in μl) and 1×PBS,and the volume is then adjusted with water. The gels are kept at 37° C.for 1 hour so as to allow them to polymerize. Next, the human veinendothelial cells (HUVECs ref: C-12200—Promocell) were seeded at 15×10³or 6×10³ cells/well in 400 or 120 μl (for the 8-well or 96-well platesrespectively) of EBM medium (Clonetics C3121)+2% FBS+10 μg/ml hEGF. Theywere stimulated with 1 or 3 ng/ml of FGF-2 (R&D systems, 133-FB-025;Invitrogen, PHG0026) for 24 h at 37° C. in the presence of 5% CO₂. After24 hours, the length of the network of microtubules formed was measuredusing a computer-assisted image analysis system (Imagenia Biocom,Courtaboeuf, France) and the total length of the pseudotubules in eachwell was determined. The average total length of the microcapillarynetwork was calculated in μm for each condition corresponding to theaverage of 6 replicates.

Stimulation with FGF2 makes it possible to induce the formation of newtubules. An FGF-R antagonist is considered to be active in this test aslong as it is capable of partially inhibiting this angiogenesis at adose less than or equal to 300 nM.

Example of Screening for FGF-R Antagonists

In this experiment, the molecules are evaluated at 3 and 30 nM oninduction of the angiogenesis of HUVEC human cells by FGF-2. CompoundsNo. 71, 72 (example 11) and 68 are declared active since they exhibit aninhibitory activity of pseudotubule formation which is greater than orequal to 20% at a dose less than or equal to 300 nM.

TABLE 1 In vitro angiogenesis of HUVEC cells stimulated with FGF-2 andeffect of FGF-R antagonists (inhibition of angiogenesis as a percentageof the control) Compounds No. 3 nM 30 nM 71 −1 41 72 36 24 68 37 52

EXAMPLE 19 FGF-2-Induced In Vitro Proliferation of HUVEC Cells

In order to demonstrate the ability of the FGF-R antagonists of thepresent invention to inhibit FGF-induced cell proliferation, in vitroproliferation experiments were carried out with human endothelial cellsof HUVEC type stimulated with FGF-2 or b-FGF.

To do this, HUVEC human vein endothelial cells (promocell, C-12200) areseeded at a rate of 5000 cells per well of a 96-well plate (Biocoatcollagen I cellware, Becton Dickinson 354650) in 100 μl of RPMI 1640deprivation medium (Invitrogen, 31872-025) supplemented with 0.5% or 1%FCS, 2 mM glutamine, 1× sodium pyruvate (Invitrogen; 11360-039) and1×NEAA (Invitrogen, 11140-035), overnight at 37° C. in the presence of5% CO₂. The following morning, the medium is suctioned-off and replacedwith 50 μl of deprivation medium containing the antagonists at a 2×concentration, to which are added 50 μl of FGF-2 (R&D systems,133-FB-025; Invitrogen, PHG0026) at 0.2 ng/ml (i.e. 2×). After 48 or 72h, 100 μl of Cell Titer-GLO™ Luminescent Cell Viability Assay (Promega,G7571) are added for 10 min in order to measure, by means of aluminometer, the amount of ATP present in the cells and which is inrelation to the number of cells per well corresponding to the cellproliferation.

The antagonists of the present invention are considered to be active aslong as they are capable of inhibiting FGF-2-induced proliferation ofHUVEC cells at a dose less than or equal to 300 nM.

Example of HUVEC Cell Proliferation Induced by FGF-2 and Inhibited byFGF-R Antagonists

Compounds No. 49 (example 4), 71 and 72 (example 11) are capable ofinhibiting the FGF-2-induced cell proliferation since, in theirpresence, a reduction in proliferation of greater than or equal to 20%is observed for doses less than or equal to 300 nM.

TABLE 2 Cell proliferation of HUVEC cells stimulated with FGF-2 andeffect of FGF-R antagonists (inhibition of proliferation as percentageof the control) Compounds No. 30 nM 300 nM 49 9 29 71 35 34 72 38 55

More generally, all the compounds according to the invention are active,at the dose of 300 nM, in in vitro angiogenesis of HUVEC cells inducedby FGF-2 or in in vitro proliferation of HUVEC cells induced by FGF-2.

EXAMPLE 20 Model of Inflammatory Angiogenesis in Mice

Angiogenesis is required for the development of chronic inflammatorydiseases such as rheumatoid arthritis. The formation of new vesselsallows not only the perfusion of pathological tissues, but also thetransport of cytokines responsible for establishing the chronicity ofthe disease.

The model described by Colville-Nash et al., in 1995, makes it possibleto study pharmacological agents capable of modulating the occurrence ofangiogenesis in an inflammatory context. The model is developed on OF1female mice (Charles River Laboratories) weighing approximately 25 g,and by groups of 12. The animals are anaesthetized with sodiumpentobarbital (60 mg/kg; Sanofi Nutrition Sante animale))intraperitoneally. An air pocket is created on the back of the mouse bysubcutaneous injection of 3 ml of air. After they have awoken, theanimals receive a treatment generally by gavage, and receive aninjection of 0.5 ml of Freund's adjuvant (Sigma) with 0.1% of croton oil(Sigma) in the pocket. Seven days later, the mice are againanaesthetized and placed on a hot plate at 40° C. One ml of carmine red(Aldrich Chemicals, 5% in 10% of gelatin) is injected into the tailvein. The animals are then placed at 4° C. for 2-3 hours. The skins arethen taken and dried for 24 h in an oven at 56° C. The dry tissues areweighed and placed in 1.8 ml of digestion solution (2 mM dithiothreitol,20 mM Na₂HPO₄, 1 mM EDTA, 12 U/ml papain) for 24 h. The dye is thendissolved in 0.2 ml of 5M NaOH. The skins are centrifuged at 2000 rpmfor 10 min at ambient temperature. The supernatants are filtered through0.2 μm cellulose acetate membranes. The filtrates are read in aspectrophotometer at 492 nm against a carmine red calibration range. Twoparameters are studyed: the dry weight of the granuloma and the amountof dye after digestion of the tissues. The results are expressed as meanvalues (±sem). The differences between the groups are tested with anANOVA followed by a Dunnett's test, of which the reference group is the“solvent control” group.

The FGF-R antagonists are evaluated between 1 and 50 mg/kg usingmethylcellulose/tween (0.6% v/v) as vehicle or any other vehicle whichallows the active ingredient to be solubilized. The molecules areadministered daily, orally (one or two times a day) by gavage. Theantagonists of the present invention are considered to be active as longas they enable a significant reduction in the angiogenic parameter, i.e.a reduction in the amount of carmine red dye in the skins of the animalstested.

Example of evaluation of FGF-R antagonists in the model of inflammatoryangiogenesis in mice. Compounds No. 49 (example 4) and 72 (example 11)at 10 mg/kg, after one week of daily treatment, significantly reduce thetwo parameters measured: the weight of the granuloma (dry weight of theskin) corresponding to the inflammation part of the model, and the dyecontent corresponding to the angiogenesis.

TABLE 3 Effect of the FGF-R antagonists, in a model of inflammatoryangiogenesis, on the dry weight of the skins or on their content ofcarmine red dye. % inhibition of % inhibition of the inflammatory theangiogenic Model of inflammatory parameter (mass parameter (dyeangiogenesis of the granuloma) content) Compound No. 49 (example 4); 4046 10 mg/kg Compound No. 223 (example 17); 25 43 10 mg/kg Compound No.72 (example 11); 38 43 10 mg/kg Compound No. 71; 30 mg/kg 28 40 CompoundNo. 149; 10 mg/kg 14 30 Compound No. 215; 10 mg/kg 21 39 Compound No. 10(example 2); 19 19 30 mg/kg

EXAMPLE 21 4T1 Orthotopic Mammary Carcinoma Model in Mice

In order to evaluate the effect of the FGF-R antagonists in a murinetumour model, 4T1 mouse mammary carcinoma cells are injected into themammary gland. The cells proliferate until the formation of a tumourafter infiltration of the cells of the tumour microenvironment.

The 4T1 cells are cultured in RPMI 1640 medium containing 10% FCS and 1%glutamine, supplemented with 1 mg/ml of geneticin. On the day of theinjection into the mouse, the 4T1 cell concentration is adjusted to2×10⁶ cells/ml in PBS in order to inject 1×10⁵ cells in 50 μl.

Mice (Balb/c, female, Charles River, approximately 8+/−2 weeks old) areanaesthetized by intraperitoneal injection of a mixture of 5% Rompun(xylazine), 10% Imalgene (ketamine) and 85% NaCl, in a proportion of 10ml/kg. The injection zone (top-right nipple) is disinfected withhexomedine. After having vortexed the cells, 50 μl are removed in asyringe and injected into the nipple with a 26G needle. The day ofinjection corresponds to D1. There are 15 mice in each group of mice (10mice will be devoted to the ELISA assays and 5 mice to the histology).The FGF-R antagonists are evaluated at between 1 and 50 mg/kg inmethylcellulose/tween (0.6% v/v) or any other vehicle which makes itpossible to solubilize the active ingredient. The molecules areadministered daily, orally (one or two times a day) by gavage, thistaking place from D5 to D21, which is the day before the samples aretaken. From D5, the tumours are measured as soon as possible, every twodays, or even every day at the end of the experiment, using a caliper(sliding caliper). It is done in the following way: the longest length(L) and the perpendicular to the centre (I) are measured in mm. Thevolume in mm³ is then defined by means of the mathematical formula whichdetermines the volume of an ellipsoid: (I²×L)×0.52. On the day thesamples are taken, generally D22, the mice are sacrificed by means of anexcess of sodium pentobarbital after having measured the volume of thetumours. The tumours are then cleared, photographed and weighed. Thelungs are also removed and the metastases are counted after boinstaining.

The antagonists of the present invention are considered to be active aslong as they allow a significant reduction in the volume of the tumourand/or any number of lung metastases.

Example of 4T1 Mammary Carcinoma in Mice

The compounds considered to be active in the inflammatory angiogenesismodel are evaluated in the 4T1 mammary carcinoma model in mice atbetween 1 and 50 mg/kg and showed a reduction in tumour volume of up to49% and a decrease in the number of lung metastases of up to 33%.

It therefore appears that the compounds of formula (I) according to thepresent invention, by virtue of their FGF antagonist effect, reduce invitro and in vivo, angiogenesis, tumour growth and metastasization.

Generally, FGFs and their receptors play an important role, by means ofautocrine, paracrine or juxtacrine secretions, in phenomena where thereis dysregulation of the stimulation of cancer cell growth. Furthermore,FGFs and their receptors affect tumour angiogenesis which plays apredominant role both on tumour growth and also on metastasizationphenomena.

Angiogenesis is a process in which new capillary vessels are generatedfrom pre-existing vessels or by mobilization and differentiation of bonemarrow cells. Thus, both uncontrolled proliferation of endothelial cellsand mobilization of angioblasts from the bone marrow are observed intumour neovascularization processes. It has been shown, in vitro and invivo, that several growth factors stimulate endothelial proliferation,and in particular FGF-1 or a-FGF and FGF-2 or b-FGF. These two factorsinduce proliferation, migration and protease production by endothelialcells in culture and neovascularization in vivo. a-FGF and b-FGFinteract with endothelial cells by means of two classes of receptors,high-affinity receptor tyrosine kinases (FGF-Rs) and low-affinityreceptors of heparin sulphate proteoglycan type (HSPGs) located at thesurface of cells and in extracellular matrices. Although the paracrinerole of these two factors on endothelial cells is widely described,these FGFs could also intervene on the cells through an autocrineprocess. Thus, FGFs and their receptors represent very relevant targetsfor therapies aimed at inhibiting angiogenesis processes (Keshet E,Ben-Sasson S A., J. Clin. Invest, (1999), Vol. 501, pp. 104-1497; PrestaM, Rusnati M, Dell'Era P, Tanghetti E, Urbinati C, Giuliani R of al, NewYork: Plenum Publishers, (2000), pp. 7-34, Billottet C, Janji B, ThieryJ. P., Jouanneau J, Oncogene, (2002) Vol. 21, pp. 8128-8139).

Moreover, systematic studies aimed at determining the expression due toFGFs and their receptors (FGF-Rs) of various types of tumour cellsdemonstrate that a cell response to these two factors is functional in alarge majority of human tumour lines studyed. These results support thehypothesis that an FGF receptor antagonist could also inhibit tumourcell proliferation (Chandler L A, Sosnowski B A, Greenlees L, Aukerman SL, Baird A, Pierce G F., Int. J. Cancer, (1999), Vol. 58, pp. 81-451).

FGFs play an important role in the growth and maintenance of prostatecells. It has been shown, both in animal models and in humans, that animpairment in the cell response to these factors plays an essential rolein the progression of prostate cancer. Specifically, in thesepathological conditions, both an increase in the production of a-FGF,b-FGF, FGF-6, FGF-8 etc., by the fibroblasts, stromal cells, residualbasal cells and endothelial cells present in the tumour and an increasein the expression of FGF receptors and ligands by the tumour cells arerecorded. Thus, a paracrine stimulation of prostate cancer cells takesplace, and this process appears to be a major component of thispathological condition. A compound which has an FGF receptor antagonistactivity, such as the compounds of the present invention, may representa therapy of choice in these pathological conditions (Girl D, RopiquetF., Clin. Cancer Res., (1999), Vol. 71, pp. 5-1063; Doll J A, Reiher FK, Crawford S E, Pins M R, Campbell S C, Bouck N P., Prostate, (2001),Vol. 305, pp. 49-293) (Sahadevan et al., 2007) (Kwabi-Addo et al.,2004).

Several studies show the presence of FGFs and of their receptors,FGF-Rs, both in human breast tumour lines (in particular MCF7) and intumour biopsies. These factors appear to be responsible, in thispathological condition, for the appearance of the very aggressivephenotype and induce a strong metastasization. Thus, a compound whichhas FGF-R receptor antagonist activity, such as the compounds of formulaI, may represent a therapy of choice in these pathological conditions(Vercoutter-Edouart A-S, Czeszak X, Crépin M, Lemoine J, Boilly B, LeBourhis X et al., Exp. Cell Res., (2001), Vol. 262, pp. 59-68)(Schwertfeger, 2009).

Cancerous melanomas are tumours which induce metastases with a highfrequency and which are very resistant to the various chemotherapytreatments. The angiogenesis processes play a predominant role in theprogression of a cancerous melanoma. Furthermore, it has been shown thatthe probability of the occurrence of metastases increases very greatlywith the increase in the vascularization of the primary tumour. Melanomacells produce and secrete various angiogenic factors, including a-FGFand b-FGF. Moreover, it has been shown that inhibition of the cellulareffect of these two factors by means of the soluble FGF-R1 receptorblocks melanoma tumour cell proliferation and survival in vitro andblocks tumour progression in vivo. Thus, a compound which has an FGFreceptor antagonist activity, such as the compounds of the presentinvention, may represent a therapy of choice in these pathologicalconditions (Rofstad E K, Halsor E F., Cancer Res., (2000); Yayon A, MaY-S, Safran M, Klagsbrun M, Halaban R., Oncogene, (1997), Vol. 14, pp.2999-3009).

Glyoma cells produce a-FGF and b-FGF in vitro and in vivo, and havevarious FGF receptors at their surface. This therefore suggests thatthese two factors play a pivotal role, by means of an autocrine andparacrine effect, in the progression of this type of tumour.Furthermore, like most solid tumours, the progression of gliomas andtheir ability to induce metastases is highly dependent on the angiogenicprocesses in the primary tumour. It has also been shown that FGF-R1receptor antisenses block human astrocytoma proliferation. In addition,naphthalenesulphonate derivatives are described for inhibiting thecellular effects of a-FGF and b-FGF in vitro and the angiogenesisinduced by these growth factors in vivo. An intracerebral injection ofthese compounds induces a very significant increase in apoptosis and aconsiderable decrease in angiogenesis, reflected by a considerableregression of gliomas in rats. Thus, a compound which has an a-FGFantagonist and/or b-FGF antagonist and/or FGF receptor antagonistactivity, such as the compounds of the present invention, may representa therapy of choice in these pathological conditions (Yamada S M,Yamaguchi F, Brown R, Berger M S, Morrison R S, Glia, (1999), Vol. 76,pp. 28-66; Auguste P, Gürsel D B, Lemière S, Reimers D, Cuevas P,Carceller F et al., Cancer Res., (2001), Vol. 26, pp. 61-1717) (Loilomeet al., 2008).

Active angiogenesis is also described for hepatocarcinomas orhepatocellular carcinoma (HCC). In vivo, tumour progression in HCCsrequires a considerable supply of oxygen and nutrients. Hepatocarcinomasare tumours which are typically angiogenic, because a drasticmodification is observed with respect to arterial vascularization, andthis results in the acquisition of an uvasive and metastatic potential(Tanaka et al., 2006). FGFs participate actively in the development oftumour angiogenesis within HCCs and are frequently associated with theinflammatory process. They are also overexpressed in the context ofchronic hepatitis and liver sclerosis (Uematsu et al., 2005) and theserum FGF level has been correlated with the clinicopathologicalprogression of HCCs. Furthermore, the FGF-R4 receptor, and also FGF-R1,have been described as participating actively in HCC tumour genesis(Huang et al., 2006) (Nicholes et al., 2002). The antagonists of thepresent invention may therefore be a treatment of choice forhepatocellular carcinomas or hepatocarcinomas.

In lung cancers of NSCLC (Non-Small Cell Lung Cancer) type, recentstudies show that b-FGF, FGF-9, FGF-R1 and FGF-R2 are regularlycoexpressed in NSCLC cancer lines and especially in those resistant toanti-EGFR treatment such as gefitinib. These expressions are connectedto the capacity for proliferation via autocrine cell signalling andanchorage-independent growth of tumours of NSCLC type and mainly thetype insensitive to treatment with gefitinib (Marek et al., 2008).Furthermore, b-FGF has been suggested as playing an important role inthe survival of NSCLC cells during treatment by chemotherapy, byinducing the overexpression of the anti-apoptotic proteins BCL-2, BCL-X,XIAP or BIRC3 (Pardo et al., 2002, 2003 and 2006). Thus, an FGF receptorantagonist, such as those of the present invention, may represent atherapy of choice for lung cancers of NSCLC type, alone or incombination with EGF receptor inhibitors or chemotherapies.

In approximately 10% of gastric cancers, this FGF-R2 gene amplificationis observed. This amplification is associated with a poor vitalprognosis for cancers of diffuse type. The proliferation of tumour cellsmay be ligand-independent or dependent on paracrine activation by FGF-7(Turner et al., 2010). The antagonists of the present invention maytherefore be a treatment of choice for gastric cancers.

More recently, the potential role of pro-angiogenic agents in leukaemiasand lymphomas has been documented. Indeed, in general, it has beenreported that cell clones in these pathological conditions can bedestroyed naturally by the immune system or switch into an angiogenicphenotype which promotes their survival and then their proliferation.This change in phenotype is induced by an overexpression of angiogenicfactors, in particular by macrophages, and/or a mobilization of thesefactors from the extracellular matrix (Thomas D A, Giles F J, Cortes J,Albitar M, Kantarjian H M., Acta Haematol, (2001), Vol. 207, pp.106-190). Among the angiogenic factors, b-FGF has been detected in manylymphoblastic and hematopoietic tumour cell lines. FGF receptors arealso present on the majority of these lines, suggesting a possibleautocrine cellular effect of a-FGF and b-FGF inducing proliferation ofthese cells. Moreover, it has been reported that bone marrowangiogenesis via paracrine effects is correlated with the progression ofsome of these pathological conditions.

More particularly, it has been shown, in CLL (chronic lymphocyticleukaemia) cells, that b-FGF induces an increase in anti-apoptoticprotein (Bcl2) expression, resulting in an increase in the survival ofthese cells, and that it therefore participates considerably in theircancerization. In addition, the b-FGF levels measured in these cells arevery well-correlated with the stage of clinical advancement of thedisease and the resistance to the chemotherapy applied in thispathological condition (fludarabine). Thus, a compound which has an FGFreceptor antagonist activity, such as the compounds of the presentinvention, may represent a therapy of choice, either alone or incombination with fludarabine or other products that are active in thispathological condition (Thomas D A, Giles F J, Cortes J, Albitar M,Kantarjian H M., Acta Haematol, (2001), Vol. 207, pp. 106-190; GabriloveJ L, Oncologist, (2001), Vol. 6, pp. 4-7).

Furthermore, it has been shown in many recent studies that FGFs andFGF-Rs participate actively in the resistance of tumour and/orendothelial cells to treatments by chemotherapy, radiotherapy or elseanti-VEGF treatments. These resistances use various cell mechanisms,such as protection against apoptosis by positive regulation of theBcl-xl protein by FGF-R4 in the case of breast cancer resistance todoxorubicin (Roidl et al., 2009) or by FGF-2 production in the case ofresistance of bladder tumours to cisplatin (Miyake at al., 1998), byactivation of the Pi3K/AKT pathway by the FGF2/FGF-R1 couple in the caseof resistance of acute myeloidal leukaemia cells to cytarabin(Karajannis at al., 2006), by stimulation of the RAS/MAP-K, PI3-K andmTOR pathway by FGF-1 for certain breast tumours resistant toanti-oestrogen treatments (Manuvakhova et al., 2006). The FGFs/FGF-Rscouple is also involved in resistance to anti-VEGF treatments in thecase of pancreatic carcinomas (Casanovas et al., 2005) or ofglioblastomas (Batchelor et al., 2007) or else in radiotherapyresistance phenomena (Gu et al., 2004; Moyal et al., 2009). Thus, thecompounds of the present invention could be combined with existingtherapies in order to limit the appearance of resistance phenomena.

Furthermore, tumour invasion, which is one of the marks of malignancy,consists of the translocation of tumour cells from the initialneoplastic locus to the surrounding host tissues, allowing the tumour topenetrate into the vascular endothelium in order to circulate and toform metastatic loci remote from the primary tumour. An increasingnumber of recent articles suggest that changes in the tissuearchitecture at the peripherary of the tumour appear to be responsiblefor the epithelial-mesenchymal transition (EMT) process. EMT is a cellprocess by which epithelial cells modulate their phenotype and acquiremesenchymal cell properties through the disruption of intercellularadhesion and an increase in cell motility, thus playing an essentialrole in tumour progression by conferring an invasive and metastaticphenotype on carcinomas. Growth factors such as FGFs participate in thiscell process by virtue of their stimulatory activity on cell migrationand invasion, but also, as regards FGF receptors, by virtue of theirability to interact with cadherins, thus facilitating tumour cellmigration (Cowin et al., 2005). The FGF-R antagonists described hereinmay be used for preventing these metastatic phases in a large number ofcancers.

A correlation exists between the bone marrow angiogenesis process and“extramedullar disease” in CML (chronic myelomonocytic leukaemia).Various studies demonstrate that the inhibition of angiogenesis, inparticular by means of a compound which has an FGF receptor antagonistactivity, could represent a therapy of choice in this pathologicalcondition.

The proliferation and migration of vascular smooth muscle cellscontributes to intimal hypertrophy of the arteries and thus plays apredominant role in atherosclerosis and in restenosis after angioplastyand endoarterectomy.

In vivo studies show, after lesion of the carotid “balloon injury”, alocal production of a-FGF and of b-FGF. In this same model, an anti-FGF2neutralizing antibody inhibits vascular smooth muscle cell proliferationand thus decreases intimal hypertrophy.

A chimeric protein consisting of FGF2 linked to a molecule such assaporin inhibits vascular smooth muscle cell proliferation in vitro andintimal hypertrophy in vivo (Epstein C E, Siegall C B, Biro S, Fu Y M,FitzGerald D., Circulation, (1991), Vol. 87, pp. 84-778; WaltenbergerJ., Circulation, (1997), pp. 96-4083).

Thus, FGF receptor antagonists, such as the compounds of the presentinvention, represent a therapy of choice, either alone or in combinationwith compounds that are antagonists of other growth factors involved inthese pathological conditions, such as PDGF, in the treatment ofpathological conditions related to vascular smooth muscle cellproliferation, such as atherosclerosis, post-angioplasty restenosis orrestenosis following the implantation of endovascular prostheses(stents) or during aortocoronary bypasses.

Cardiac hypertrophy occurs in response to a stress of the ventricularwall induced by an overload in terms of pressure or volume. Thisoverload can be the consequence of numerous physiopathological states,such as hypertension, AC (aortic coarctation), myocardial infarction,and various vascular disorders. The consequences of this pathologicalcondition are morphological, molecular and functional changes such ascardiac myocyte hypertrophy, matrix protein accumulation and foetal genereexpression. b-FGF is implicated in this pathological condition.Specifically, the addition of b-FGF to cultures of newborn ratcardiomyocytes modifies the profile of the genes corresponding to thecontractile proteins, resulting in a foetal-type gene profile. In acomplementary manner, adult rat myocytes show a hypertrophic responseunder the effect of b-FGF, this response being blocked by anti-b-FGFneutralizing antibodies. Experiments carried out in vivo inb-FGF-knock-out transgenic mice show that b-FGF is the major factorstimulating cardiac myocyte hypertrophy in this pathological condition(Schultz Je J, Witt S A, Nieman M L, Reiser P J, Engle S J, Zhou M etal., J. Clin. Invest., (1999), Vol. 19, pp. 104-709). Thus, a compound,such as the compounds of the present invention, which has an FGFreceptor antagonist activity represents a therapy of choice in thetreatment of heart failure and any other pathological conditionassociated with cardiac tissue degeneration. This treatment could becarried out alone or in combination with the common treatments(beta-blockers, diuretics, angiotensic antagonists, antiarrythmics,anti-calcium agents, antithrombotics, etc.).

Vascular disorders due to diabetes are characterized by an impairment ofvascular reactivity and of blood flow, hyperpermeability, an exacerbatedproliferative response and an increase in matrix protein deposits. Morespecifically, a-FGF and b-FGF are present in the preretinol membranes ofpatients having diabetic retinopathies, in the membranes of theunderlying capillaries and in the vitreous humour of patients sufferingfrom proliferative retinopathies. A soluble FGF receptor capable ofbinding both a-FGF and b-FGF is developed in diabetes-related vasculardisorders (Tilton R G, Dixon R A F, Brock T A., Exp. Opin. Invest.Drugs, (1997), Vol. 84, pp. 6-1671). Thus, a compound, such as thecompounds of formula I, which has an FGF receptor antagonist activityrepresents a therapy of choice, either alone or in combination withcompounds that are antagonists of other growth factors involved in thesepathological conditions, such as VEGF.

Fibrosis is the abnormal formation of scar tissues following a tissuelesion, and results in a chronic and progressive impairment of theaffected organs that can result in serious dysfunction of the affectedorgan. It can occur in all tissues, but is mainly prevalent in organsexposed to chemical or biological attacks, such as the lungs, the skin,the kidneys, the digestive tract, the liver, etc. FGFs participate inthis cell process by promoting the production and accumulation ofextracellular matrices by fibroblasts, the proliferation of saidfibroblasts and infiltration into many organs such as the kidneys or thelungs (Khalil et al., 2005) (Strutz et al., 2003). Antagonists of theactivity of these FGFs, such as the molecules of the present invention,may be used alone or in combination in the treatment of fibrosis.

Rheumatoid arthritis (RA) is a chronic disease with an unknown etiology.Although it affects many organs, the most serious form of RA is aprogressive synovial inflammation of the joints resulting indestruction. Angiogenesis appears to considerably affect the progressionof this pathological condition. Thus, a-FGF and b-FGF have been detectedin the synovial tissue and in the joint fluid of patients suffering fromRA, indicating that this growth factor is involved in the initiationand/or the progression of this pathological condition. In models of AIA(adjuvant-induced model of arthritis) in rats, it has been shown thatthe overexpression of b-FGF increases the severity of the disease,whereas an anti-b-FGF neutralizing antibody blocks the progression of RA(Malemud, 2007) (Yamashita A, Yonemitsu Y, Okano S, Nakagawa K,Nakashima Y, Irisa T et al., J. Immunol., (2002), Vol. 57, pp. 168-450;Manabe N, Oda H, Nakamura K, Kuga Y, Uchida S, Kawaguchi H, Rheumatol,(1999), Vol. 20, pp. 38-714). Thus, the compounds according to theinvention represent a therapy of choice in this pathological condition.

Recent scientific articles document the involvement of b-FGF inneuropathic pain. Specifically, an increase in astroglial b-FGFproduction is observed in astrocytes following a spinal cord lesion(Madiai et al., 2003). This b-FGF contributes to neuropathic pain due tocontact or allodynia. Treatment using an anti-FGF2 neutralizing antibodyreduces this mechanical allodynia (Madiai et al., 2005). The antagonistsof the present invention are treatments of choice for pain by inhibitingthe effect of FGF-2 on these receptors.

It has also been described that the level of growth factors having apro-angiogenic activity, such as FGF-1 and -2, are greatly increased inthe synovial fluid of patients suffering from osteoarthritis. In thistype of pathological condition, a considerable modification is recordedin the balance between the pro- and anti-angiogenic factors inducing theformation of new vessels, and consequently, the vascularization ofnonvascularized structures, such as joint cartilages or intervertebraldiscs. Thus, angiogenesis represents a key factor in bone formation(osteophytes), thus contributing to the progression of the disease.Additionally, the inervation of the new vessels can also contribute tothe chronic pain associated with this pathological condition (Walsh DA., Curr Opin Rheumatol. 2004 September; 16(5):609-15). Thus, thecompounds according to the invention represent a therapy of choice inthis pathological condition.

IBD (inflammatory bowel disease) includes two forms of chronicinflammatory diseases of the intestine: UC (ulcerative colitis) andCrohn's disease (CD). IBD is characterized by an immune dysfunctionreflected by an inappropriate production of inflammatory cytokinesinducing the establishment of a local microvascular system. Thisangiogenesis of inflammatory origin results in an intestinal ischemiainduced by vasoconstriction. High circulating and local levels of b-FGFhave been measured in patients suffering from these pathologicalconditions (Kanazawa S, Tsunoda T, Onuma E, Majima T, Kagiyama M, KkuchiK., American Journal of Gastroenterology, (2001), Vol. 28, pp 96-822;Thorn M, Raab Y, Larsson A, Gerdin B, Hallgren R., Scandinavian Journalof Gastroenterology, (2000), Vol. 12, pp. 35-408). The compounds of theinvention which exhibit a high anti-angiogenic activity in aninflammatory angiogenesis model represent a therapy of choice in thesepathological conditions.

Another disease which has a considerable inflammatory component and forwhich a strong implication of FGFs and FGF-Rs is described is benignprostatic hyperplasia (BPH). BPH is a disease related to ageing which ischaracterized by hyperplasia of the glandular tissues and of the stromaaround the urethra until it becomes obstructed. At the cellular level,this pathological condition involves hyperplasia of the basal cells, anincrease in the stromal mass, amplified matrix deposit or else areduction in tissue elasticity (Untergasser et al., 2005). FGFsparticipate in the development of this disease by stimulating theproliferation of the prostatic stroma and epithelial cells, and inparticular FGF-7 or KGF, but also FGF-2 or FGF-17 (Wang 2008, Boget2001, Giri 2001). In addition, FGFs promote the transdifferentiationstep by modifying epithelial cell/stromal cell interactions, incombination with TGF-β (Untergasser 2005). Finally, certain receptors,such as FGF-R1, are overexpressed in BPH, promoting induction of thepathological condition and potentiating the paracrine effects of FGF-2(Boget 2001). An antagonist of the effect of these FGFs is therefore atreatment of choice for benign prostatic hyperplasia.

Psoriasis is a chronic skin disease caused by a hyperproliferation ofthe epidermal keratinocytes, while clear cell acanthoma (CCA) is abenign neoplasm of the epidermis which also involves an abnormalproliferation of keratinocytes. These two skin diseases have similarhistological characteristics despite different underlying causes: athickening of the epidermis, inflammatory infiltrations of lymphocytesand neutrophils, dilation and tortuosity of the papillary capillaries.In both cases, KGF or FGF-7 μlays a predominant role in the developmentof the pathological condition (Kovacs et al., 2006) (Finch et al.,1997). The use of the antagonists of the present invention may make itpossible to slow down the development of such skin diseases.

FGF-R1, -R2 and -R3 receptors are involved in chronogenesis andosteogenesis processes. Mutations resulting in the expression of FGF-Rsthat are always activated have been connected to a large number of humangenetic diseases reflected by malformations of the skeleton, such asPfeiffer syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weisssyndrome and Bear-Stevenson cutis gyrate syndrome. Some of thesemutations affect more particularly the FGF-R3 receptor, resulting inparticular in achondroplasias (ACH), hyperchondroplasias (HCH) and TD(thanatophoric dysplasia); ACH being the most common form of dwarfism.From a biochemical point of view, the sustained activation of thesereceptors takes place via a dimerization of the receptor in the absenceof ligand (Chen L., Adar R., Yang X. Monsonego E. O., LI C., Hauschka P.V, Yagon A. and Deng C. X., (1999), The Journ. Of Clin. Invest., Vol.104, n° 11, pp. 1517-1525). Thus, the compounds of the invention whichexhibit an FGF antagonist or FGF receptor antagonist activity and whichinhibit FGF-R-dependent intracellular signalling represent a therapy ofchoice in these pathological conditions.

It is also known that adipose tissue is one of the rare tissues that, inadults, can develop or regress. This tissue is highly vascularized and avery dense network of microvessels surrounds each adipocyte. Theseobservations have resulted in the testing of the effect ofanti-angiogenic agents on adipose tissue development in adults. Thus, itappears that, in pharmacological models in ob/ob mice, the inhibition ofangiogenesis is reflected by significant weight loss in the mice(Rupnick M A et al, (2002), PNAS, Vol. 99, n°16, pp. 10730-10735).Furthermore, FGFs appear to be key regulators of adipogenesis in humans(Hutley et al., 2004). Thus, an FGF receptor antagonist compound whichhas a powerful anti-angiogenic activity may represent a therapy ofchoice in obesity-related pathological conditions.

By virtue of their low toxicity and their pharmacological and biologicalproperties, the compounds of the present invention are of use in thetreatment and prevention of any carcinoma which has a high degree ofvascularization, such as lung, breast, prostate, oesophageal,pancreatic, liver, colon or kidney carcinomas, or which inducesmetastases, such as colon, breast, liver or stomach carcinomas, ormelanomas, or which is sensitive to a-FGF or to b-FGF in an autocrinemanner or else in pathological conditions of glioma type, lymphomas andleukaemias or, finally, in any therapy-resistance phenomenon. Thesecompounds represent a therapy of choice, either alone or in combinationwith a chemotherapy, a radiotherapy or any other suitable treatment. Thecompounds according to the invention are also of use in the treatmentand prevention of cardiovascular diseases, such as atherosclerosis, orrestenosis post-angioplasty, in the treatment of diseases related tocomplications occurring following the implantation of endovascularstents and/or aortocoronary bypasses or other vascular grafts, andcardiac hypertrophy or vascular complications of diabetes, such asdiabetic retinopathies. The compounds according to the invention arealso of use in the treatment and prevention of chronic inflammatorydiseases such as rheumatoid arthritis, IBD or benign prostatichyperplasia. Finally, the compounds according to the invention can beused in the treatment and prevention of achondroplasias (ACH),hypochondroplasias (HCH) and TD (thanatophoric dysplasia), as also inthe treatment of obesity.

The products according to the invention are also of use in the treatmentand prevention of macular degeneration, in particular age-relatedmacular degeneration (or ARMD). A major characteristic of the loss ofsight in adults is the neovascularization and the subsequenthaemorrhages which cause considerable functional disorders in the eyeand which are reflected by early blindness. Recently, studying themechanisms involved in ocular neovascularization phenomena has made itpossible to demonstrate the involvement of pro-angiogenic factors inthese pathological conditions. By using a laser-induced choroidialneoangiogenesis model, it has been possible to confirm that the productsaccording to the invention also make it possible to modulateneovascularization of the choroid.

Moreover, the products of the invention can be used in the treatment orprevention of thrombopenias due in particular to anticancerchemotherapy. It has in fact been demonstrated that the products of theinvention can improve circulating platelet levels during chemotherapy.

Finally, the products according to the invention are of use in thetreatment and prevention of skin diseases, such as psoriasis or clearcell acanthoma, in combating the progression of liver, kidney or lungfibrosis, and also in the treatment of neuropathic pain.

A subject of the invention is, according to another of its aspects,medicaments which comprise a compound of formula (I), or an additionsalt thereof with a pharmaceutically acceptable acid or base, or else ahydrate or a solvate of the compound of formula (I).

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active ingredient, a compoundof formula (I) according to the invention. These pharmaceuticalcompositions contain an effective dose of at least one compoundaccording to the invention, or a pharmaceutically acceptable salt or ahydrate or solvate of said compound, and also at least onepharmaceutically acceptable excipient. Said excipients are selected,according to the pharmaceutical form and the method of administrationdesired, from the usual excipients which are known to those skilled inthe art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredient of formula (I) above, or optional salt, solvate orhydrate thereof, can be administered in unit administration form, as amixture with conventional pharmaceutical excipients, to animals and tohuman beings for the prophylaxis or the treatment of the disorders orthe diseases mentioned above.

The suitable unit administration forms comprise forms for oraladministration, such as tablets, soft or hard gel capsules, powders,granules and oral solutions or suspensions, sublingual, buccal,intratracheal, intraocular or intranasal administration forms, forms foradministration by inhalation, topical, transdermal, subcutaneous,intramuscular or intravenous administration forms, rectal administrationforms, and implants. For topical application, the compounds according tothe invention can be used in creams, gels, ointments or lotions.

The pharmaceutical compositions according to the present invention arepreferably administered orally.

By way of example, a unit administration form of a compound according tothe invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscaramellose 6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

The present invention also relates to a pharmaceutical composition asdefined above, as a medicament.

A subject of the present invention is also the use of a compound offormula (I), as defined above, for use thereof in the treatment andprevention of diseases requiring a modulation of FGFs.

A subject of the present invention is also the use of a compound offormula (I), as defined above, for use thereof in the treatment andprevention of cancers, in particular carcinomas which have a high degreeof vascularization, such as lung, breast, prostate, pancreatic, colon,kidney and oesophageal carcinomas, cancers which induce metastases, suchas colon cancer, liver cancer and stomach cancer, melanomas, gliomas,lymphomas and leukaemias.

A compound of formula (I) according to the present invention can beadministered alone or in combination with one or more compound(s) whichhas (have) an anti-angiogenic activity or with one or more cytotoxiccompound(s) (chemotherapy), or else in combination with a radiationtreatment. Thus, a subject of the present invention is also the use of acompound of formula (I), as defined above, in combination with one ormore anticancer active ingredient(s) and/or with radiotherapy.

A subject of the present invention is also the use of a compound offormula (I), as defined above, in the treatment and prevention ofcardiovascular diseases, such as atherosclerosis or post-angioplastyrestenosis, diseases related to complications occurring following theimplantation of endovascular stents and/or aortocoronary bypasses orother vascular grafts, cardiac hypertrophy, or vascular complications ofdiabetes, such as diabetic retinopathies.

A subject of the present invention is also the use of a compound offormula (I), as defined above, in the treatment or prevention of chronicinflammatory diseases such as rheumatoid arthritis or IBD.

A subject of the present invention is also the use of a compound offormula (I), as defined above, in the treatment or prevention ofosteoarthritis, achondroplasias (ACH), hypochondroplasias (HCH) and TD(thanatophoric dysplasia).

A subject of the present invention is also the use of a compound offormula (I), as defined above, in the treatment or prevention ofobesity.

A subject of the present invention is also the use of a compound offormula (I), as defined above, in the treatment or prevention of maculardegeneration, such as age-related macular degeneration (ARMD).

The compositions according to the invention, for oral administration,contain recommended doses of 0.01 to 700 mg. There may be particularcases where higher or lower dosages are appropriate; such dosages do notdepart from the context of the invention. According to the usualpractice, the dosage appropriate for each patient is determined by thephysician according to the method of administration and the age, weightand response of the patient, and also according to the degree ofprogression of the disease.

According to another of its aspects, the present invention also relatesto a method for treating the pathological conditions indicated above,which comprises the administration, to a patient, of an effective doseof a compound according to the invention, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof.

1-14. (canceled)
 15. A method of treating or preventing diseasesrequiring a modulation of b-FGFs in a patient in need thereof comprisingadministering to said patent a therapeutically effective amount of acompound of formula (I):

in which: R₁ represents a hydrogen or halogen atom, an alkyl groupoptionally substituted with —COOR₅, an alkenyl group optionallysubstituted with —COOR₅, a —COOR₅ or —CONR₅R₆ group, an —NR₅COR₆ or—NR₅—SO₂R₆ group, or an aryl group or a heteroaryl group, said aryl orheteroaryl group being optionally substituted with one or more groupsselected from: halogen atoms, alkyl groups, cycloalkyl groups, —COOR₅,—CF₃, —OCF₃, —CN, —C(NH₂)NOH, —OR₅, —O-Alk-COOR₅, —O-Alk-NR₅R₆,—O-Alk-NR₇R₈, -Alk-COOR₅, —CONR₅R₆, —CO—NR₅—OR₆, —CO—NR₅—SO₂R₇,—CONR₅-Alk-NR₅R₆, —CONR₅-Alk-NR₇R₈, -Alk-NR₅R₆, —NR₅R₆, —NC(O)N(CH₃)₂,—CO-Alk, —CO(Alk)_(n)OH, COO-Alk-NR₅R₆ COO-Alk-NR₇R₈ and 5-memberedheteroaryl groups, said heteroaryl groups being optionally substitutedwith one or more groups selected from halogen atoms and alkyl, —CF₃,—CN, —COOR₅, -Alk-OR₅, -Alk-COOR₅, —CONR₅R₆, —CONR₇R₈, —CO—NR₅—OR₆,—CO—NR₅—SO₂R₆, —NR₅R₆ and -Alk-NR₅R₆ groups, or with a hydroxyl group orwith an oxygen atom, n is an integer ranging from 1 to 3, R and R₃together form, with the carbon atoms of the phenyl nucleus to which theyare attached, a 6-membered nitrogenous heterocycle corresponding to oneof formula (A), (B) or (C) below:

in which the wavy lines represent the phenyl nucleus to which R₂ and R₃are attached and: R_(a) represents a hydrogen atom or an alkyl,haloalkyl, -Alk-CF₃, -Alk-COOR₅, -Alk′-COOR₅, -Alk-CONR₅R₆,-Alk′-CONR₅R₆, -Alk-CONR₇R₈, -Alk-NR₅R₆, -AlkCONR₅—OR₆, -Alk-NR₇R₈,-Alk-cycloalkyl, -Alk-O—R₅, -Alk-S—R₅, -Alk-CN, —OR₅, -OAlkCOOR₅,—NR₅R₆, —NR₅—COOR₆, -Alk-aryl, -Alk-O-aryl, -Alk-O-heteroaryl,-Alk-heteroaryl or heteroaryl group, where the aryl or heteroaryl groupis optionally substituted with one or more halogen atoms and/or alkyl,cycloalkyl, —CF₃, —OCF₃, —O—R₅ or —S—R₅ groups, R_(a′) represents ahydrogen atom or a linear, branched, cyclic or partially cyclic alkylgroup, or an -Alk-OR₅, -Alk-NR₅R₆ or -Alk-NR₇R₈ group, R_(a′) beingoptionally substituted with one or more halogen atoms, R_(b) representsa hydrogen atom or an alkyl or -Alk-COOR₅ group, R_(b′) represents ahydrogen atom or an alkyl, haloalkyl, cycloalkyl, phenyl or -Alk-COOR₅group, R_(c) represents a hydrogen atom or an alkyl, —CN, —COOR₅,—CO—NR₅R₆, —CONR₇R₈—CO—NR₅-Alk-NR₅R₆, —CONR₅-Alk-OR₅, —CONR₅SO₂R₅,-Alk-aryl or -Alk-heteroaryl group, where the aryl or heteroaryl groupis optionally substituted with one or more halogen atoms and/or alkyl,cycloalkyl, —CF₃, —OCF₃, —O-alkyl or —S-alkyl groups, R_(c′) representsa hydrogen atom or an alkyl group, R_(c″) represents a hydrogen atom oran alkyl, alkenyl, haloalkyl, cycloalkyl, -Alk-NR₅R₆, -Alk-NR₇R₈,-Alk-OR₅ or -Alk-SR₅ group, R₄, located on position 6, 7 or 8 of theimidazopyridine nucleus, represents: a hydrogen atom, a —COOR₅ group, a—CO—NR₅-Alk-NR₅R₆ group, a —CO—NR₅-Alk-NR₇R₈ group, or a —CO—NR₅-Alk-OR₆group, R₅ and R₆, which may be identical or different, representhydrogen atoms, haloalkyl groups or alkyl groups, cycloalkyl groups oran Ms group, R₇ and R₈, which may be identical or different, representhydrogen atoms or alkyl or phenyl groups, or else R₇ and R₈ togetherform a 3- to 8-membered saturated ring which can optionally contain aheteroatom, Alk represents a linear or branched alkylene chain, and Alk′represents a linear, branched, cyclic or partially cyclic alkylenechain, optionally in the form of a pharmaceutically acceptable saltthereof; optionally in combination with one or more suitable inertexcipients.
 16. A method of treating or preventing cancer in a patientin need thereof comprising administering to said patent atherapeutically effective amount of a compound of formula (I):

in which: R₁ represents a hydrogen or halogen atom, an alkyl groupoptionally substituted with —COOR₅, an alkenyl group optionallysubstituted with —COOR₅, a —COOR₅ or —CONR₅R₆ group, an —NR₅COR₆ or—NR₅—SO₂R₆ group, or an aryl group or a heteroaryl group, said aryl orheteroaryl group being optionally substituted with one or more groupsselected from: halogen atoms, alkyl groups, cycloalkyl groups, —COOR₅,—CF₃, —CN, —C(NH₂)NOH, —OR₅, —O-Alk-COOR₅, —O-Alk-NR₅R₆, —O-Alk-NR₇R₈,-Alk-COOR₅, —CONR₅R₆, —CO—NR₅—OR₆, —CO—NR₅—SO₂R₇, —CONR₅-Alk-NR₅R₆,—CONR₅-Alk-NR₇R₈, -Alk-NR₅R₆, —NR₅R₆, —NC(O)N(CH₃)₂, —CO-Alk,—CO(OAlk)_(n)OH, COO-Alk-NR₅R₆, COO-Alk-NR₇R₈ and 5-membered heteroarylgroups, said heteroaryl groups being optionally substituted with one ormore groups selected from halogen atoms and alkyl, —CF₃, —CN, —COOR₅,-Alk-COOR₅, —CONR₅R₆, —CONR₇R₈, —CO—NR₅—OR₆, —CO—NR₅—SO₂R₆, —NR₅R₆ and-Alk-NR₅R₆ groups, or with a hydroxyl group or with an oxygen atom, n isan integer ranging from 1 to 3, R2 and R₃ together form, with the carbonatoms of the phenyl nucleus to which the are attached, a 6-memberednitrogenous heterocycle corresponding to one of formula (A), (B) or (C)below:

in which the wavy lines represent the phenyl nucleus to which R₂ and R₃are attached and: R_(a) represents a hydrogen atom or an alkyl,haloalkyl, -Alk-CF₃, -Alk-COOR₅, -Alk′-COOR₅, -Alk-CONR₅R₆,-Alk′-CONR₅R₆, -Alk-CONR₇R₈, -Alk-NR₅R₆, -AlkCONR₅—OR₆, -Alk-NR₇R₈,-Alk-cycloalkyl, -Alk-O—R₅, -Alk-S—R₅, -Alk-CN, —OR₅, -OAlkCOOR₅,—NR₅R₆, —NR₅—COOR₆, -Alk-aryl, -Alk-O-aryl, -Alk-O-heteroaryl,-Alk-heteroaryl or heteroaryl group, where the aryl or heteroaryl groupis optionally substituted with one or more halogen atoms and/or alkyl,cycloalkyl, —CF₃, —OCF₃, —O—R₅ or —S—R₅ groups, R_(a′) represents ahydrogen atom or a linear, branched, cyclic or partially cyclic alkylgroup, or an -Alk-OR₅, -Alk-NR₅R₆ or -Alk-NR₇R₈ group, R_(a′) beingoptionally substituted with one or more halogen atoms, R_(b) representsa hydrogen atom or an alkyl or -Alk-COOR₅ group, R_(b′) represents ahydrogen atom or an alkyl, haloalkyl, cycloalkyl, phenyl or -Alk-COOR₅group, R_(c) represents a hydrogen atom or an alkyl, —CN, —COOR₅,—CO—NR₅R₆, —CONR₇R₈—CO—NR₅-Alk-NR₅R₆, —CONR₅-Alk-OR₅, —CONR₅SO₂R₅,-Alk-aryl or -Alk-heteroaryl group, where the aryl or heteroaryloptionally substituted with one or more halogen atoms and/or alkyl,cycloalkyl, —CF₃, —OCF₃, —O-alkyl or —S-alkyl groups, R_(c′) representsa hydrogen atom or an alkyl group, R_(c″) represents a hydrogen atom oran alkyl, alkenyl, haloalkyl, cycloalkyl, -Alk-NR₅R₆, -Alk-NR₇R₈,-Alk-OR₅ or -Alk-SR₅ group, R₄, located on position 6, 7 or 8 of theimidazopyridine nucleus, represents: a hydrogen atom, a —COOR₅ group, a—CO—NR₅-Alk-NR₅R₆ group, —CO—NR₅-Alk-NR₇R₈ group, or a —CO—NR₅-Alk-OR₆group, R₅ and R₆, which may be identical or different, representhydrogen atoms, haloalkyl groups or alkyl groups, cycloalkyl groups oran Ms group, R₇ and R₈, which may be identical or different, representhydrogen atoms or alkyl or phenyl groups, or else R₇ and R₈ togetherform a 3- to 8-membered saturated ring which can optionally contain aheteroatom, Alk represents a linear or branched alkylene chain, and Alk′represents a linear, branched, cyclic or partially cyclic alkylenechain, optionally in the form of a pharmaceutically acceptable saltthereof; optionally in combination with one or more suitable inertexcipients.
 17. The method according to claim 16 further comprisingadministering the compound of formula (I) in combination with one ormore anticancer active ingredient(s) and/or with radiotherapy and/orwith an anti-VEGF treatment.
 18. A method of treating or preventingcardiovascular diseases, diseases related to complications that occurfollowing the implantation of endovascular stents and/or aortocoronarybypasses or other vascular grafts, cardiac hypertrophy, vascularcomplications of diabetes, liver, kidney and lung fibroses, neuropathicpain, chronic inflammatory diseases, prostatic hyperplasia, psoriasis,clear cell acanthoma, osteoarthritis, achondroplasias (ACH),hypochondroplasias (HCH), TD (thanatophoric dysplasia), obesity, andmacular degeneration, in a patient in need thereof comprisingadministering to said patent a therapeutically effective amount of acompound of formula (I):

in which: R₁ represents a hydrogen or halogen atom, an alkyl groupoptionally substituted with —COOR₅, an alkenyl group optionallysubstituted with —COOR₅, a —COOR₅ or —CONR₅R₆ group, an —NR₅COR₆ or—NR₅—SO₂R₆ group, or an aryl group or a heteroaryl group, said aryl orheteroaryl group being optionally substituted with one or more groupsselected from: halogen atoms, alkyl groups, cycloalkyl groups, —COOR₅,—CF₃, —OCF₃, —CN, —C(NH₃)NOH, —OR₅, —O-Alk-COOR₅, —O-Alk-NR₅R₆,—O-Alk-NR₇R₈, -Alk-COOR₅, —CONR₅R₆, —CO—NR₅—OR₆, —CO—NR₅—SO₂R₇,—CONR₅-Alk-NR₅R₆, —CONR₅-Alk-NR₇R₈, -Alk-NR₅R₆, —NR₅R₆, —NC(O)N(CH₃)₂,—CO-Alk, —CO(OAlk)_(n)OH, COO-Alk-NR₅R₆, COO-Alk-NR₇R₈ and 5-memberedheteroaryl groups, said heteroaryl groups being optionally substitutedwith one or more groups selected from halogen atoms and alkyl, —CF₃,—CN, —COOR₅, -Alk-OR₅, -Alk-COOR₅, —CONR₅R₆, —CONR₇R₈, —CO—NR₅—OR₆,—CO—NR₅—SO₂R₆, —NR₅R₆ and -Alk-NR₅R₆ groups, or with a hydroxyl group orwith an oxygen atom, n is an integer ranging from 1 to 3, R₂ and R₃together form, with the carbon atoms of the phenyl nucleus to which theyare attached, a 6-membered nitrogenous heterocycle corresponding to oneof formula (A), (B) or (C) below:

in which the wavy lines represent the phenyl nucleus to which R₂ and R₃are attached and: R_(a) represents a hydrogen atom or an alkyl,haloalkyl, -Alk-CF₃, -Alk-COOR₅, -Alk′-COOR₅, -Alk-CONR₅R₆,-Alk′-CONR₅R₆, -Alk-CONR₇R₈, -Alk-NR₅R₆, -AlkCONR₅—OR₆, -Alk-NR₇R₈,-Alk-cycloalkyl, -Alk-O—R₅, -Alk-S—R₅, -Alk-CN, —OR₅, -OAlkCOOR₅,—NR₅R₆, —NR₅—COOR₆, -Alk-aryl, -Alk-O-aryl, -Alk-O-heteroaryl,-Alk-heteroaryl or heteroaryl group, where the aryl or heteroaryl groupis optionally substituted with one or more halogen atoms and/or alkyl,cycloalkyl, —CF₃, —OCF₃, —O—R₅ or —S—R₅ groups, R_(a′) represents ahydrogen atom or a linear, branched, cyclic or partially cyclic alkylgroup, or an -Alk-OR₅, -Alk-NR₅R₆ or -Alk-NR₇R₈ group, R_(a′) beingoptionally substituted with one or more halogen atoms, R_(b) representsa hydrogen atom or an alkyl or -Alk-COOR₅ group, R_(b′) represents ahydrogen atom or an alkyl, haloalkyl, cycloalkyl, phenyl or -Alk-COOR₅group, R_(c) represents a hydrogen atom or an alkyl, —CN, —COOR₅,—CO—NR₅R₆, —CONR₇R₈—CO—NR₅-Alk-NR₅R₆, —CONR₅-Alk-OR₅, —CONR₅SO₂R₅,-Alk-aryl or -Alk-heteroaryl group, where the aryl or heteroaryl groupis optionally substituted with one or more halogen atoms and/or alkyl,cycloalkyl, —CF₃, —OCF₃, —O-alkyl or —S-alkyl groups, R_(c′) representsa hydrogen atom or an alkyl group, R_(c″) represents a hydrogen atom oran alkyl, alkenyl, haloalkyl, cycloalkyl, -Alk-NR₅R₆, -Alk-NR₇R₈,-Alk-OR₅ or -Alk-SR₅ group, R₄, located on position 6, 7 or 8 of theimidazopyridine nucleus, represents: a hydrogen atom, a —COOR₅ group, a—CO—NR₅-Alk-NR₅R₆ group, a —CO—NR₅-Alk-NR₇R₈ group, or a —CO—NR₅-Alk-OR₆group, R₅ and R₆, which may be identical or different, representhydrogen atoms, haloalkyl groups or alkyl groups, cycloalkyl groups oran Ms group, R₇ and R₈, which may be identical or different, representhydrogen atoms or alkyl or phenyl groups, or else R₇ and R₈ togetherform a 3- to 8-membered saturated ring which can optionally contain aheteroatom, Alk represents a linear or branched alkylene chain, and Alk′represents a linear, branched, cyclic or partially cyclic alkylenechain, optionally in the form of a pharmaceutically acceptable saltthereof; optionally in combination with one or more suitable inertexcipients.
 19. (canceled)
 20. The method according to claim 16 whereinthe cancer comprises carcinomas which have a high degree ofvascularization, cancers which induce metastases, melanomas, gliomas,lymphomas, leukaemias, and thrombopenias.
 21. The method according toclaim 20 wherein the carcinomas which have a high degree ofvascularisation comprise lung, breast, prostate, pancreatic, colon,kidney, and oesophageal carcinomas.
 22. The method according to claim 20wherein the cancers which induce metastases comprise colon cancer, livercancer, and stomach cancer.
 23. The method according to claim 18 whereinthe cardiovascular diseases comprise atherosclerosis andpost-angioplasty restenosis.
 24. The method according to claim 18wherein the vascular complications of diabetes comprise diabeticretinopathies.
 25. The method according to claim 18 wherein the maculardegeneration comprises age-related macular degeneration (ARMD).